US20130331287A1 - Autoimmune Antibodies - Google Patents

Autoimmune Antibodies Download PDF

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US20130331287A1
US20130331287A1 US13/911,392 US201313911392A US2013331287A1 US 20130331287 A1 US20130331287 A1 US 20130331287A1 US 201313911392 A US201313911392 A US 201313911392A US 2013331287 A1 US2013331287 A1 US 2013331287A1
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seq
autoantibody
egfr
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human subject
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Peter Berndt
Barbara Klughammer
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Hoffmann La Roche Inc
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Hoffmann La Roche Inc
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6854—Immunoglobulins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2863—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for growth factors, growth regulators
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/564—Immunoassay; Biospecific binding assay; Materials therefor for pre-existing immune complex or autoimmune disease, i.e. systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, rheumatoid factors or complement components C1-C9
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/57407—Specifically defined cancers
    • G01N33/57423—Specifically defined cancers of lung
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/705—Assays involving receptors, cell surface antigens or cell surface determinants
    • G01N2333/71—Assays involving receptors, cell surface antigens or cell surface determinants for growth factors; for growth regulators

Definitions

  • the present invention provides methods for identifying patients diagnosed with non-small cell lung cancer who will most benefit from treatment with erlotinib comprising detecting autoantibodies in blood serum of said patients.
  • Tarceva® is an orally active, potent, inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase (TKI).
  • EGFR epidermal growth factor receptor
  • TKI tyrosine kinase
  • Erlotinib hydrochloride is the active ingredient in Tarceva®, which is approved as single agent treatment for patients with advanced non-small cell lung cancer (NSCLC) after treatment with chemotherapy, as maintenance treatment for patients not progressing during chemotherapy (1 st line maintenance) or after failure of chemotherapy (2 nd /3 rd line maintenance).
  • Tarceva® is also approved as first line treatment for patients whose tumor harbors an EGFR activating mutation in the EU.
  • the mammalian immune system contains a specialized arm that recognizes proteins induced by cellular transformation (neo-antigens) and effectively eliminates cells that express these neo-antigens against which tolerance has not established during development.
  • This arm of the immune system is thought to be effective against viral infections, spontaneous chromosomal and genomic rearrangements caused by errors of the cell division machinery, or carcinogen-induced transforming mutations.
  • cytotoxic immune response which is mediated by the recognition of the unusual proteins displayed on MHCI complexes by CD8 + T-cells—is fast and effective
  • a sustained response against virus infections or aberrant cellular clones requires the co-stimulatory effect of CD4 + T-helper cells which are activated after presentation of extracellular peptides (which can stem from cells lysed in the first phase of the cytotoxic immune response) via MHCII complexes of professional antigen presenting cells. Additionally, these cells are able to induce a lasting B-cell response and antibodies to viral or aberrant proteins.
  • Cancer autoantibodies are well known diagnostic entities in cancer. Many cancer autoantibodies are proteins that are normally expressed in embryonic tissues and therefore represent a “foreign” protein against which immune tolerance is not established. The shedding of these proteins to the bloodstream late in cancer history leads to a humoral immune response. A typical example is the common cancer marker CEA (cancer embryonic antigen). Tumors frequently exhibit faulty protein processing.
  • CEA cancer embryonic antigen
  • Prominent examples include proteins that are incorrectly cleaved by cell localization proteases (the presence of autoantibodies against the N-terminal sequence of p53 which is normally cleaved after the protein is targeted to the nucleus is one of the most specific biomarkers of lung cancer) or incorrectly glycosylated by cellular glycosylases (anti-MUC1-antibodies against a form of MUC1 that is incorrectly O-glycosylated is a biomarker for a variety of cancers).
  • WO2011073905 5 relates to tumor markers associated with the progression of a cancer disease from a less progressed stage to a more progressed stage.
  • Present invention solves that problem in that it provides a method of diagnosis of cancer in a human subject.
  • Present invention solves that problem in that it provides a method of diagnosis of non-small cell lung cancer in a human subject.
  • Present invention solves that problem in that it provides a method of diagnosis of non-small cell lung cancer in a human subject by providing antibodies against mutated EGFR sequences.
  • a patient identified by a method as described herein is a patient, in particular a NSCLC patient who will respond to the treatment with erlotinib or a pharmaceutically acceptable salt thereof, in particular erlotinib hydrochloride.
  • EGFR is normally bound to the cell membrane and not shed to the bloodstream.
  • EGFR is a normal adult protein that is found in large quantities in some adult tissues. Immune tolerance is expected to be established against this protein and many of its variants. Almost all of the sequences belong to the cytoplasmic part of the molecule and are invisible to professional antigen presenting cells. The mutations affect only a small part of the EGFR molecule.
  • a level of said autoantibody representative for a human subject of a healthy population refers to an estimate of the mean level of the autoantibody in serum of a population of patients who do not suffer from NSCLC.
  • a level of said autoantibody representative for a NSCLC patient refers to an estimate of the mean level of the autoantibody in serum of a population of patients who suffer from NSCLC.
  • overall survival refers to the length of time from diagnosis of disease during and after treatment the patient survives.
  • OS all survival
  • progression-free survival refers to the length of time from diagnosis of disease during and after treatment during which, according to the assessment of the treating physician or investigator, the patient's disease does not become worse, i.e., does not progress.
  • a patient's progression-free survival is improved or enhanced if the patient belongs to a subgroup of patients that has a longer length of time during which the disease does not progress as compared to the average or mean progression free survival time of a control group of similarly situated patients.
  • patient refers to any single mammal for which treatment is desired.
  • the “patient” is a human subject. More particularly, the patient is a human subject suffering from cancer, in particular NSCLC.
  • autoantibody is a type of protein manufactured by the immune system of a patient that is directed against one or more of the patient's own proteins.
  • amino acid denotes the group of naturally occurring carboxy a-amino acids comprising alanine (three letter code: ala, one letter code: A), arginine (arg, R), asparagine (asn, N), aspartic acid (asp, D), cysteine (cys, C), glutamine (gln, Q), glutamic acid (glu, E), glycine (gly, G), histidine (his, H), isoleucine (ile, I), leucine (leu, L), lysine (lys, K), methionine (met, M), phenylalanine (phe, F), proline (pro, P), serine (ser, S), threonine (thr, T), tryptophan (trp, W), tyrosine (tyr, Y), and valine (val, V).
  • “therapy” or “treatment” refers to clinical intervention in an attempt to alter the natural course of a disease in the individual being treated, and can be performed either for prophylaxis or during the course of clinical pathology. Desirable effects of treatment include, but are not limited to, preventing occurrence or recurrence of disease, alleviation of symptoms, diminishment of any direct or indirect pathological consequences of the disease, preventing metastasis, decreasing the rate of disease progression, amelioration or palliation of the disease state, and remission or improved prognosis.
  • gene as used herein comprises variants of the gene.
  • variant relates to nucleic acid sequences which are substantially similar to the nucleic acid sequences given by the GenBank accession number.
  • substantially similar is well understood by a person skilled in the art.
  • a gene variant may be an allele which shows nucleotide exchanges compared to the nucleic acid sequence of the most prevalent allele in the human population.
  • a substantially similar nucleic acid sequence has a sequence similarity to the most prevalent allele of at least 80%, preferably at least 85%, more preferably at least 90%, most preferably at least 95%.
  • variants is also meant to relate to splice variants.
  • mutation refers to changes in a genomic sequence. These random sequences can be defined as sudden and spontaneous changes in the cell. Mutation can result in several different types of change in sequences; these can either have no effect, alter the product of a gene, or prevent the gene from functioning properly or completely.
  • sequences can either have no effect, alter the product of a gene, or prevent the gene from functioning properly or completely.
  • sequences can either have no effect, alter the product of a gene, or prevent the gene from functioning properly or completely.
  • sequence mutation refers to a change in the genetic structure that is neither inherited nor passed to offspring.
  • recommending a treatment refers to using the information or data generated relating to the level or presence of a biomarker or an autoantibody in a sample of a patient to identify the patient as suitably treated or not suitably treated with a therapy.
  • the therapy may comprise a drug.
  • the information or data may be in any form, written, oral or electronic.
  • using the information or data generated includes communicating, presenting, reporting, storing, sending, transferring, supplying, transmitting, delivering, dispensing, or combinations thereof.
  • communicating, presenting, reporting, storing, sending, transferring, supplying, transmitting, delivering, dispensing, or combinations thereof are performed by a computing device, analyzer unit or combination thereof.
  • communicating, presenting, reporting, storing, sending, transferring, supplying, transmitting, delivering, dispensing, or combinations thereof are performed by a laboratory or medical professional.
  • the information or data includes a comparison of the level of said biomarker or autoantibody to a reference level.
  • the information or data includes an indication that said biomarker or autoantibody is present or absent in the sample.
  • the information or data includes an indication that the patient is suitably treated or not suitably treated with a therapy comprising said drug.
  • the therapy is erlotinib.
  • providing a diagnosis refers to using the information or data generated relating to the level or presence of a biomarker or an autoantibody in a sample of a patient to diagnose a disease in the patent.
  • the information or data may be in any form, written, oral or electronic.
  • using the information or data generated includes presenting, reporting, storing, sending, transferring, supplying, transmitting, delivering, dispensing, or combinations thereof.
  • presenting, reporting, storing, sending, transferring, supplying, transmitting, delivering, dispensing, or combinations thereof are performed by a computing device, analyzer unit or combination thereof.
  • presenting, reporting, storing, sending, transferring, supplying, transmitting, delivering, dispensing, or combinations thereof are performed by a laboratory or medical professional.
  • the information or data includes a comparison of the level of said biomarker or autoantibody to a reference level.
  • the information or data includes an indication that said biomarker or autoantibody is present or absent in the sample.
  • the information or data includes an indication that the patient is diagnosed with said disease. In some embodiments, said disease is non-small cell lung cancer.
  • biopsy material had been collected and the tumor cells have been tested for the presence of the most frequent somatic mutations, i.e. a deletion at exon 19, and a point mutation at exon 21.
  • serum samples had been collected at various time points (pre-dose, day 8, day 22 and progression) from all patients and were assessed for autoantibodies against EGFR.
  • autoantigenic peptide sequences that predict development of rash, or prolonged progression free or overall survival inevitably include a set of sequences that are derived from the EGFR sequence starting at position 737 and extending through 756.
  • These peptides include a number of sequence variants, but inevitably include sequences that have a deletion at position 746-750 or close nearby (Table 2).
  • somatic EGFR mutation occurs only in the tumor, and therefore, if it induces an autoantibody which can be detected in the patient's serum it can be used to draw conclusions about the presence of an exon 19 mutation or exon 21 mutation in the NSCLC tissue, which is well known to predict increased progression free survival and superiority of tyrosine kinase monotherapy over chemotherapy (Hovi and Reck 2011 11 ). 11 Hovi, D. and M. Reck (2011). “Mutations in the epidermal growth factor receptor gene in non-small cell lung cancer: Impact on treatment beyond gefitinib and erlotinib.” Advances in Therapy 28(2): 126-133
  • the autoantibody can be detected using a standard blood sample from the patient without the need to obtain tumor cells with a biopsy. This is a large advantage over the current practice, as recovery rates of useful tumor samples even in clinical studies do not exceed 50% (Reck, Hermes et al. 2011 12 ). 12 Reck, M., A. Hermes, et al. (2011). “Tissue sampling in lung cancer: A review in light of the MERIT experience.” Lung Cancer 74(1): 1-6
  • Anti-EGFR autoantibodies can be detected in blood samples of NSCLC patients at higher concentrations than in healthy controls ( FIG. 1 ).
  • peptide sequences have been identified that yield consecutive regions of high immunogenicity with large differences between patient and healthy controls sera. Consecutive sequence stretches were identified, where ratios of individual peptide signals in more than 30% of the cancer patients to maximum value in controls was larger than 8 (Table 1).
  • FIG. 2 Regression analysis has identified significant evidence that the presence of antibodies to the peptides influence both, progression free survival (PFS) and overall survival (OS) ( FIG. 2 ). Although the number of samples is small in comparison to the number of peptides, many covariates need to be considered and none of the individual peptides reach sufficient statistical significance, we surprisingly found that when combining overlapping information from various independent statistical approaches, selection of a relevant peptide from the many candidates obtained after univariate analysis is possible.
  • FIG. 3 illustrates the process that led to selection of the candidate sequences listed in Table 2. Sequences listed in Table 2 or any continuous subsequences thereof longer than 8 amino acids are candidate sequences.
  • EGFR peptide sequences selected from Seq. Id. No. 1-Seq. Id. No. 15 are consecutive sequences with high autoantigenicity in NLSCL patients.
  • EGFR peptide sequences selected from Seq. Id. No. 16-Seq. Id. No. 517 are useful for predicting the occurrence and grade of adverse events like rash to erlotinib treatment.
  • EGFR peptide sequences selected from Seq. Id. No. 518-Seq. Id. No. 602 are antigenic sequences influencing, in particular extending, progression free and overall survival of NSCLC patients, in particular mutated EGFR peptide sequences Seq. Id. No. 554, Seq. Id. No. 555, Seq. Id. No. 556, Seq. Id. No. 557, Seq. Id. No. 558, Seq. Id. No. 559 and Seq. Id. No. 560, as well as EGFR peptide sequences Seq. Id. No. 519, Seq. Id. No. 520, Seq. Id. No. 521 and Seq. Id. No. 561.
  • EGFR peptide sequences selected from Seq. Id. No. 603-Seq. Id. No. 619 have high predictive potential for prolonged progression free survival in patients with EGFR mutations that develop rash.
  • Antibodies against these peptide sequences most likely influence PFS and OS if they are present in patients. Tests that detect the presence of these antibodies in patient sera could be used to guide treatment and stratify patients into treatment groups.
  • Present invention provides a method of diagnosis of non-small cell lung cancer in a human subject comprising:
  • Present invention provides a method of diagnosis of non-small cell lung cancer in a human subject comprising:
  • Present invention provides a method of diagnosis of non-small cell lung cancer in a human subject comprising:
  • a certain embodiment of the present invention provides a method as described above, wherein said treatment is erlotinib.
  • a certain embodiment of present invention provides a method as described herein, wherein the level of an autoantibody recognizing mutated human EGFR is measured.
  • a certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes a mutated EGFR peptide is selected from the group consisting of Seq. Id. No. 1, Seq. Id. No. 2, Seq. Id. No. 4, Seq. Id. No. 5, Seq. Id. No. 6, Seq. Id. No. 7, Seq. Id. No. 15, Seq. Id. No. 16, Seq. Id. No. 17, Seq. Id. No. 18, Seq. Id. No. 19, Seq. Id. No. 20, Seq. Id. No. 21, Seq. Id. No. 22, Seq. Id. No. 23, Seq. Id. No. 24, Seq. Id.
  • Seq. Id. No. 26 Seq. Id. No. 27, Seq. Id. No. 28, Seq. Id. No. 29, Seq. Id. No. 30, Seq. Id. No. 31, Seq. Id. No. 32, Seq. Id. No. 33, Seq. Id. No. 34, Seq. Id. No. 35, Seq. Id. No. 36, Seq. Id. No. 37, Seq. Id. No. 38, Seq. Id. No. 39, Seq. Id. No. 40, Seq. Id. No. 41, Seq. Id. No. 42, Seq. Id. No. 43, Seq. Id. No. 44, Seq.
  • Seq. Id. No. 119 Seq. Id. No. 120, Seq. Id. No. 121, Seq. Id. No. 122, Seq. Id. No. 123, Seq. Id. No. 124, Seq. Id. No. 125, Seq. Id. No. 126, Seq. Id. No. 127, Seq. Id. No. 128, Seq. Id. No. 129, Seq. Id. No. 130, Seq. Id. No. 131, Seq. Id. No. 132, Seq. Id. No. 133, Seq. Id. No. 134, Seq. Id. No. 135, Seq. Id.
  • Seq. Id. No. 154 Seq. Id. No. 155, Seq. Id. No. 156, Seq. Id. No. 157, Seq. Id. No. 158, Seq. Id. No. 159, Seq. Id. No. 160, Seq. Id. No. 161, Seq. Id. No. 162, Seq. Id. No. 163, Seq. Id. No. 164, Seq. Id. No. 165, Seq. Id. No. 166, Seq. Id. No. 167, Seq. Id. No. 168, Seq. Id. No. 169, Seq. Id. No. 170, Seq. Id.
  • Seq. Id. No. 190 Seq. Id. No. 191, Seq. Id. No. 192, Seq. Id. No. 193, Seq. Id. No. 194, Seq. Id. No. 195, Seq. Id. No. 196, Seq. Id. No. 197, Seq. Id. No. 198, Seq. Id. No. 199, Seq. Id. No. 200, Seq. Id. No. 201, Seq. Id. No. 202, Seq. Id. No. 203, Seq. Id. No. 204, Seq. Id. No. 205, Seq. Id. No. 206, Seq.
  • Seq. Id. No. 225 Seq. Id. No. 226, Seq. Id. No. 227, Seq. Id. No. 228, Seq. Id. No. 229, Seq. Id. No. 230, Seq. Id. No. 231, Seq. Id. No. 232, Seq. Id. No. 233, Seq. Id. No. 234, Seq. Id. No. 235, Seq. Id. No. 236, Seq. Id. No. 237, Seq. Id. No. 238, Seq. Id. No. 239, Seq. Id. No. 240, Seq. Id. No. 241, Seq. Id. No.
  • Seq. Id. No. 335 Seq. Id. No. 336, Seq. Id. No. 337, Seq. Id. No. 338, Seq. Id. No. 339, Seq. Id. No. 340, Seq. Id. No. 341, Seq. Id. No. 342, Seq. Id. No. 343, Seq. Id. No. 344, Seq. Id. No. 345, Seq. Id. No. 346, Seq. Id. No. 347, Seq. Id. No. 348, Seq. Id. No. 349, Seq. Id. No. 350, Seq. Id. No. 351, Seq.
  • Seq. Id. No. 408 Seq. Id. No. 409, Seq. Id. No. 410, Seq. Id. No. 411, Seq. Id. No. 412, Seq. Id. No. 413, Seq. Id. No. 414, Seq. Id. No. 415, Seq. Id. No. 416, Seq. Id. No. 417, Seq. Id. No. 418, Seq. Id. No. 419, Seq. Id. No. 420, Seq. Id. No. 421, Seq. Id. No. 422, Seq. Id. No. 423, Seq. Id. No. 424, Seq. Id. No.
  • Seq. Id. No. 426 Seq. Id. No. 427, Seq. Id. No. 428, Seq. Id. No. 429, Seq. Id. No. 430, Seq. Id. No. 431, Seq. Id. No. 432, Seq. Id. No. 433, Seq. Id. No. 434, Seq. Id. No. 435, Seq. Id. No. 436, Seq. Id. No. 437, Seq. Id. No. 438, Seq. Id. No. 439, Seq. Id. No. 440, Seq. Id. No. 441, Seq. Id. No. 442, Seq. Id.
  • Seq. Id. No. 444 Seq. Id. No. 445, Seq. Id. No. 446, Seq. Id. No. 447, Seq. Id. No. 448, Seq. Id. No. 449, Seq. Id. No. 450, Seq. Id. No. 451, Seq. Id. No. 452, Seq. Id. No. 453, Seq. Id. No. 454, Seq. Id. No. 455, Seq. Id. No. 456, Seq. Id. No. 457, Seq. Id. No. 458, Seq. Id. No. 459, Seq. Id. No. 460, Seq. Id. No.
  • Seq. Id. No. 462 Seq. Id. No. 463, Seq. Id. No. 464, Seq. Id. No. 465, Seq. Id. No. 466, Seq. Id. No. 467, Seq. Id. No. 468, Seq. Id. No. 469, Seq. Id. No. 470, Seq. Id. No. 471, Seq. Id. No. 472, Seq. Id. No. 473, Seq. Id. No. 474, Seq. Id. No. 475, Seq. Id. No. 476, Seq. Id. No. 477, Seq. Id. No. 478, Seq. Id.
  • Seq. Id. No. 480 Seq. Id. No. 481, Seq. Id. No. 482, Seq. Id. No. 483, Seq. Id. No. 484, Seq. Id. No. 485, Seq. Id. No. 486, Seq. Id. No. 487, Seq. Id. No. 488, Seq. Id. No. 489, Seq. Id. No. 490, Seq. Id. No. 491, Seq. Id. No. 492, Seq. Id. No. 493, Seq. Id. No. 494, Seq. Id. No. 495, Seq. Id. No. 496, Seq. Id. No.
  • Seq. Id. No. 536 Seq. Id. No. 537, Seq. Id. No. 538, Seq. Id. No. 539, Seq. Id. No. 540, Seq. Id. No. 541, Seq. Id. No. 542, Seq. Id. No. 543, Seq. Id. No. 544, Seq. Id. No. 545, Seq. Id. No. 546, Seq. Id. No. 547, Seq. Id. No. 548, Seq. Id. No. 549, Seq. Id. No. 550, Seq. Id. No. 551, Seq. Id. No. 552, Seq. Id. No. 553, Seq. Id.
  • Seq. Id. No. 555 Seq. Id. No. 557, Seq. Id. No. 559, Seq. Id. No. 560, Seq. Id. No. 562, Seq. Id. No. 563, Seq. Id. No. 564, Seq. Id. No. 565, Seq. Id. No. 567, Seq. Id. No. 568, Seq. Id. No. 569, Seq. Id. No. 570, Seq. Id. No. 571, Seq. Id. No. 572, Seq. Id. No. 573, Seq. Id. No. 574, Seq. Id. No.
  • a certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes a mutated EGFR peptide that is selected from the groups consisting of Seq. Id. No. 1, Seq. Id. No. 2, Seq. Id. No. 4, Seq. Id. No. 5, Seq. Id. No. 6, Seq. Id. No. 7 and Seq. Id. No. 15.
  • a certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes a mutated EGFR peptide that is selected from the group consisting of Seq. Id. No. 16, Seq. Id. No. 17, Seq. Id. No. 18, Seq. Id. No. 19, Seq. Id. No. 20, Seq. Id. No. 21, Seq. Id. No. 22, Seq. Id. No. 23, Seq. Id. No. 24, Seq. Id. No. 25, Seq. Id. No. 26, Seq. Id. No. 27, Seq. Id. No. 28, Seq. Id. No. 29, Seq. Id. No. 30, Seq. Id. No. 31, Seq. Id. No. 32, Seq.
  • Seq. Id. No. 214 Seq. Id. No. 215, Seq. Id. No. 216, Seq. Id. No. 217, Seq. Id. No. 218, Seq. Id. No. 219, Seq. Id. No. 220, Seq. Id. No. 221, Seq. Id. No. 222, Seq. Id. No. 223, Seq. Id. No. 224, Seq. Id. No. 225, Seq. Id. No. 226, Seq. Id. No. 227, Seq. Id. No. 228, Seq. Id. No. 229, Seq. Id. No. 230, Seq. Id. No.
  • Seq. Id. No. 250 Seq. Id. No. 251, Seq. Id. No. 252, Seq. Id. No. 253, Seq. Id. No. 254, Seq. Id. No. 255, Seq. Id. No. 256, Seq. Id. No. 257, Seq. Id. No. 258, Seq. Id. No. 259, Seq. Id. No. 260, Seq. Id. No. 261, Seq. Id. No. 262, Seq. Id. No. 263, Seq. Id. No. 264, Seq. Id. No. 265, Seq. Id. No. 266, Seq. Id. No.
  • Seq. Id. No. 505 Seq. Id. No. 506, Seq. Id. No. 507, Seq. Id. No. 508, Seq. Id. No. 509, Seq. Id. No. 510, Seq. Id. No. 511, Seq. Id. No. 512, Seq. Id. No. 513, Seq. Id. No. 514, Seq. Id. No. 515, Seq. Id. No. 516 and Seq. Id. No. 517.
  • a certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes a mutated EGFR peptide that is selected from the group consisting of Seq. Id. No. 518, Seq. Id. No. 522, Seq. Id. No. 523, Seq. Id. No. 524, Seq. Id. No. 526, Seq. Id. No. 527, Seq. Id. No. 528, Seq. Id. No. 529, Seq. Id. No. 530, Seq. Id. No. 531, Seq. Id. No. 532, Seq. Id. No. 533, Seq. Id. No. 534, Seq. Id.
  • Seq. Id. No. 575 Seq. Id. No. 576, Seq. Id. No. 577, Seq. Id. No. 578, Seq. Id. No. 579, Seq. Id. No. 580, Seq. Id. No. 581, Seq. Id. No. 582, Seq. Id. No. 583, Seq. Id. No. 584, Seq. Id. No. 585, Seq. Id. No. 586, Seq. Id. No. 587, Seq. Id. No. 588, Seq. Id. No. 589, Seq. Id. No. 590, Seq. Id. No.
  • a certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes a mutated EGFR peptide that is selected from the group consisting of Seq. Id. No. 604, Seq. Id. No. 605, Seq. Id. No. 606, Seq. Id. No. 607, Seq. Id. No. 608, Seq. Id. No. 609, Seq. Id. No. 610, Seq. Id. No. 611, Seq. Id. No. 612, Seq. Id. No. 613, Seq. Id. No. 614, Seq. Id. No. 615, Seq. Id. No. 616, Seq. Id. No. 617, Seq. Id. No. 618 and Seq. Id. No. 619.
  • a certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide that is selected from the group consisting of Seq. Id. No. 519, Seq. Id. No. 520, Seq. Id. No. 521, and Seq. Id. No. 561.
  • a certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes a mutated EGFR peptide that is selected from the group consisting of Seq. Id. No. 554, Seq. Id. No. 555, Seq. Id. No. 556, Seq. Id. No. 557, Seq. Id. No. 558, Seq. Id. No. 559, and Seq. Id. No. 560.
  • a certain embodiment of present invention provides a method as described herein, wherein the level of an autoantibody in the blood sample of the human subject is 5 times higher than the level of said autoantibody representative for a human subject of a healthy population.
  • a certain embodiment of present invention provides erlotinib or a pharmaceutically acceptable salt thereof, in particular erlotinib hydrochloride, for use in treating a NSCLC patient identified by a method as described herein comprising administering erlotinib or a pharmaceutically acceptable salt thereof, in particular erlotinib hydrochloride to the patient.
  • a certain embodiment of present invention provides the use of an autoantibody for predicting the response of a NSCLC patient to erlotinib or a pharmaceutically acceptable salt thereof, in particular erlotinib hydrochloride, treatment, which antibody was identified by a method as described herein.
  • a certain embodiment of present invention provides a kit for detecting in a blood sample of the human subject a level of one or more autoantibodies selected from the group of autoantibodies recognizing mutated human EGFR, wherein an increased level of said autoantibodies selected from the group of autoantibodies recognizing mutated human EGFR in the blood sample of the human subject compared to a level of said autoantibodies representative for a human subject of a healthy population is indicative for non-small cell lung cancer.
  • a certain embodiment of present invention provides a kit as described herein, wherein the autoantibody recognizes a mutated EGFR peptide that is selected from the group consisting of Seq. Id. No. 1, Seq. Id. No. 2, Seq. Id. No. 4, Seq. Id. No. 5, Seq. Id. No. 6, Seq. Id. No. 7 and Seq. Id. No. 15.
  • a certain embodiment of present invention provides a kit as described herein, wherein the autoantibody recognizes a mutated EGFR peptide that is selected from the group consisting of Seq. Id. No. 16, Seq. Id. No. 17, Seq. Id. No. 18, Seq. Id. No. 19, Seq. Id. No. 20, Seq. Id. No. 21, Seq. Id. No. 22, Seq. Id. No. 23, Seq. Id. No. 24, Seq. Id. No. 25, Seq. Id. No. 26, Seq. Id. No. 27, Seq. Id. No. 28, Seq. Id. No. 29, Seq. Id. No. 30, Seq. Id. No. 31, Seq.
  • Seq. Id. No. 142 Seq. Id. No. 143, Seq. Id. No. 144, Seq. Id. No. 145, Seq. Id. No. 146, Seq. Id. No. 147, Seq. Id. No. 148, Seq. Id. No. 149, Seq. Id. No. 150, Seq. Id. No. 151, Seq. Id. No. 152, Seq. Id. No. 153, Seq. Id. No. 154, Seq. Id. No. 155, Seq. Id. No. 156, Seq. Id. No. 157, Seq. Id. No. 158, Seq.
  • Seq. Id. No. 304 Seq. Id. No. 305, Seq. Id. No. 306, Seq. Id. No. 307, Seq. Id. No. 308, Seq. Id. No. 310, Seq. Id. No. 311, Seq. Id. No. 312, Seq. Id. No. 313, Seq. Id. No. 314, Seq. Id. No. 315, Seq. Id. No. 316, Seq. Id. No. 317, Seq. Id. No. 318, Seq. Id. No. 319, Seq. Id. No. 320, Seq. Id. No. 321, Seq. Id. No.
  • Seq. Id. No. 359 Seq. Id. No. 360, Seq. Id. No. 361, Seq. Id. No. 362, Seq. Id. No. 363, Seq. Id. No. 364, Seq. Id. No. 365, Seq. Id. No. 366, Seq. Id. No. 367, Seq. Id. No. 368, Seq. Id. No. 369, Seq. Id. No. 371, Seq. Id. No. 372, Seq. Id. No. 374, Seq. Id. No. 375, Seq. Id. No. 376, Seq. Id. No. 377, Seq. Id. No.
  • Seq. Id. No. 415 Seq. Id. No. 416, Seq. Id. No. 417, Seq. Id. No. 418, Seq. Id. No. 419, Seq. Id. No. 420, Seq. Id. No. 421, Seq. Id. No. 422, Seq. Id. No. 423, Seq. Id. No. 424, Seq. Id. No. 425, Seq. Id. No. 426, Seq. Id. No. 427, Seq. Id. No. 428, Seq. Id. No. 429, Seq. Id. No. 430, Seq. Id. No. 431, Seq.
  • Seq. Id. No. 450 Seq. Id. No. 451, Seq. Id. No. 452, Seq. Id. No. 453, Seq. Id. No. 454, Seq. Id. No. 455, Seq. Id. No. 456, Seq. Id. No. 457, Seq. Id. No. 458, Seq. Id. No. 459, Seq. Id. No. 460, Seq. Id. No. 461, Seq. Id. No. 462, Seq. Id. No. 463, Seq. Id. No. 464, Seq. Id. No. 465, Seq. Id. No. 466, Seq. Id. No.
  • Seq. Id. No. 504 Seq. Id. No. 505, Seq. Id. No. 506, Seq. Id. No. 507, Seq. Id. No. 508, Seq. Id. No. 509, Seq. Id. No. 510, Seq. Id. No. 511, Seq. Id. No. 512, Seq. Id. No. 513, Seq. Id. No. 514, Seq. Id. No. 515, Seq. Id. No. 516 and Seq. Id. No. 517.
  • a certain embodiment of present invention provides a kit as described herein, wherein the autoantibody recognizes a mutated EGFR peptide that is selected from the group consisting of Seq. Id. No. 518, Seq. Id. No. 522, Seq. Id. No. 523, Seq. Id. No. 524, Seq. Id. No. 526, Seq. Id. No. 527, Seq. Id. No. 528, Seq. Id. No. 529, Seq. Id. No. 530, Seq. Id. No. 531, Seq. Id. No. 532, Seq. Id. No. 533, Seq. Id. No. 534, Seq. Id.
  • Seq. Id. No. 575 Seq. Id. No. 576, Seq. Id. No. 577, Seq. Id. No. 578, Seq. Id. No. 579, Seq. Id. No. 580, Seq. Id. No. 581, Seq. Id. No. 582, Seq. Id. No. 583, Seq. Id. No. 584, Seq. Id. No. 585, Seq. Id. No. 586, Seq. Id. No. 587, Seq. Id. No. 588, Seq. Id. No. 589, Seq. Id. No. 590, Seq. Id. No.
  • a certain embodiment of present invention provides a kit as described herein, wherein the autoantibody recognizes a mutated EGFR peptide that is selected from the group consisting of Seq. Id. No. 604, Seq. Id. No. 605, Seq. Id. No. 606, Seq. Id. No. 607, Seq. Id. No. 608, Seq. Id. No. 609, Seq. Id. No. 610, Seq. Id. No. 611, Seq. Id. No. 612, Seq. Id. No. 613, Seq. Id. No. 614, Seq. Id. No. 615, Seq. Id. No. 616, Seq. Id. No. 617, Seq. Id. No. 618 and Seq. Id. No. 619.
  • a certain embodiment of present invention provides a kit as described herein, wherein the autoantibody recognizes a mutated EGFR peptide that is selected from the group consisting of Seq. Id. No. 554, Seq. Id. No. 555, Seq. Id. No. 556, Seq. Id. No. 557, Seq. Id. No. 558, Seq. Id. No. 559, and Seq. Id. No. 560.
  • a certain embodiment of present invention provides a kit as described herein, wherein the autoantibody recognizes an EGFR peptide that is selected from the group consisting of Seq. Id. No. 519, Seq. Id. No. 520, Seq. Id. No. 521, and Seq. Id. No. 561.
  • a level of an autoantibody selected from the group of autoantibodies recognizing human EGFR wherein an increased level of said autoantibody selected from the group of autoantibodies recognizing human EGFR in the blood sample of the human subject compared to a level of said autoantibody representative for a human subject of a healthy population is indicative for non-small cell lung cancer, in particular wherein the level of an autoantibody recognizing human EGFR is measured.
  • Present invention provides a method of diagnosis of non-small cell lung cancer in a human subject comprising:
  • Present invention provides a method of diagnosis of non-small cell lung cancer in a human subject comprising:
  • a certain embodiment of the present invention provides a method as described above, wherein said treatment is erlotinib.
  • a certain embodiment of present invention provides a method as described above, wherein the autoantibody recognizes an EGFR peptide is selected from the group consisting of Seq. Id. No. 1, Seq. Id. No. 2, Seq. Id. No. 3, Seq. Id. No. 4, Seq. Id. No. 5, Seq. Id. No. 6, Seq. Id. No. 7, Seq. Id. No. 8, Seq. Id. No. 9, Seq. Id. No. 10, Seq. Id. No. 11, Seq. Id. No. 12, Seq. Id. No. 13, Seq. Id. No. 14, Seq. Id. No. 15, Seq. Id. No. 16, Seq. Id. No.
  • Seq. Id. No. 166 Seq. Id. No. 167, Seq. Id. No. 168, Seq. Id. No. 169, Seq. Id. No. 170, Seq. Id. No. 171, Seq. Id. No. 172, Seq. Id. No. 173, Seq. Id. No. 174, Seq. Id. No. 175, Seq. Id. No. 176, Seq. Id. No. 177, Seq. Id. No. 178, Seq. Id. No. 179, Seq. Id. No. 180, Seq. Id. No. 181, Seq. Id. No. 182, Seq. Id.
  • Seq. Id. No. 292 Seq. Id. No. 292, Seq. Id. No. 293, Seq. Id. No. 294, Seq. Id. No. 295, Seq. Id. No. 296, Seq. Id. No. 297, Seq. Id. No. 298, Seq. Id. No. 299, Seq. Id. No. 300, Seq. Id. No. 301, Seq. Id. No. 302, Seq. Id. No. 303, Seq. Id. No. 304, Seq. Id. No. 305, Seq. Id. No. 306, Seq. Id. No. 307, Seq. Id. No. 308, Seq. Id. No.
  • Seq. Id. No. 310 Seq. Id. No. 311, Seq. Id. No. 312, Seq. Id. No. 313, Seq. Id. No. 314, Seq. Id. No. 315, Seq. Id. No. 316, Seq. Id. No. 317, Seq. Id. No. 318, Seq. Id. No. 319, Seq. Id. No. 320, Seq. Id. No. 321, Seq. Id. No. 322, Seq. Id. No. 323, Seq. Id. No. 324, Seq. Id. No. 325, Seq. Id. No. 326, Seq. Id. No.
  • Seq. Id. No. 328 Seq. Id. No. 329, Seq. Id. No. 330, Seq. Id. No. 331, Seq. Id. No. 332, Seq. Id. No. 333, Seq. Id. No. 334, Seq. Id. No. 335, Seq. Id. No. 336, Seq. Id. No. 337, Seq. Id. No. 338, Seq. Id. No. 339, Seq. Id. No. 340, Seq. Id. No. 341, Seq. Id. No. 342, Seq. Id. No. 343, Seq. Id. No. 344, Seq. Id.
  • Seq. Id. No. 400 Seq. Id. No. 401, Seq. Id. No. 402, Seq. Id. No. 403, Seq. Id. No. 404, Seq. Id. No. 405, Seq. Id. No. 406, Seq. Id. No. 407, Seq. Id. No. 408, Seq. Id. No. 409, Seq. Id. No. 410, Seq. Id. No. 411, Seq. Id. No. 412, Seq. Id. No. 413, Seq. Id. No. 414, Seq. Id. No. 415, Seq. Id. No. 416, Seq. Id.
  • Seq. Id. No. 489 Seq. Id. No. 490, Seq. Id. No. 491, Seq. Id. No. 492, Seq. Id. No. 493, Seq. Id. No. 494, Seq. Id. No. 495, Seq. Id. No. 496, Seq. Id. No. 497, Seq. Id. No. 498, Seq. Id. No. 499, Seq. Id. No. 500, Seq. Id. No. 501, Seq. Id. No. 502, Seq. Id. No. 503, Seq. Id. No. 504, Seq. Id. No. 505, Seq. Id. No.
  • Seq. Id. No. 560 Seq. Id. No. 561, Seq. Id. No. 562, Seq. Id. No. 563, Seq. Id. No. 564, Seq. Id. No. 565, Seq. Id. No. 566, Seq. Id. No. 567, Seq. Id. No. 568, Seq. Id. No. 569, Seq. Id. No. 570, Seq. Id. No. 571, Seq. Id. No. 572, Seq. Id. No. 573, Seq. Id. No. 574, Seq. Id. No. 575, Seq. Id. No. 576, Seq.
  • Seq. Id. No. 594 Seq. Id. No. 595, Seq. Id. No. 596, Seq. Id. No. 597, Seq. Id. No. 598, Seq. Id. No. 599, Seq. Id. No. 600, Seq. Id. No. 601, Seq. Id. No. 602, Seq. Id. No. 603, Seq. Id. No. 604, Seq. Id. No. 605, Seq. Id. No. 606, Seq. Id. No. 607, Seq. Id. No. 608, Seq. Id. No. 609, Seq. Id. No. 610, Seq. Id. No. 611, Seq. Id. No.
  • a certain embodiment of present invention provides a method as described above, wherein the autoantibody recognizes an EGFR peptide that is selected from the group consisting of Seq. Id. No. 3, Seq. Id. No. 8, Seq. Id. No. 9, Seq. Id. No. 10, Seq. Id. No. 11, Seq. Id. No. 12, Seq. Id. No. 13, Seq. Id. No. 14, Seq. Id. No. 64, Seq. Id. No. 102, Seq. Id. No. 309, Seq. Id. No. 370, Seq. Id. No. 373, Seq. Id. No. 519, Seq. Id. No. 520, Seq. Id.
  • a certain embodiment of present invention provides a kit for detecting in a blood sample of the human subject a level of one or more autoantibodies selected from the group of autoantibodies recognizing human EGFR, wherein an increased level of said autoantibodies selected from the group of autoantibodies recognizing human EGFR in the blood sample of the human subject compared to a level of said autoantibodies representative for a human subject of a healthy population is indicative for non-small cell lung cancer.
  • a certain embodiment of present invention provides a kit as described above, wherein the autoantibody recognizes an EGFR peptide that is selected from the group consisting of Seq. Id. No. 3, Seq. Id. No. 8, Seq. Id. No. 9, Seq. Id. No. 10, Seq. Id. No. 11, Seq. Id. No. 12, Seq. Id. No. 13, Seq. Id. No. 14, Seq. Id. No. 64, Seq. Id. No. 102, Seq. Id. No. 309, Seq. Id. No. 370, Seq. Id. No. 373, Seq. Id. No. 519, Seq. Id. No. 520, Seq. Id.
  • a certain embodiment of present invention provides a kit according as described herein, wherein the autoantibody recognizes a mutated EGFR peptide that is selected from Seq. Id. No. 554, Seq. Id. No. 555, Seq. Id. No. 556, Seq. Id. No. 557, Seq. Id. No. 558, Seq. Id. No. 559, and Seq. Id. No. 560.
  • a certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 518.
  • a certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 519.
  • a certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 520.
  • a certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 521.
  • a certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 522.
  • a certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 523.
  • a certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 524.
  • a certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 525.
  • a certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 526.
  • a certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 527.
  • a certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 528.
  • a certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 529.
  • a certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 530.
  • a certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 531.
  • a certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 532.
  • a certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 533.
  • a certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 534.
  • a certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 535.
  • a certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 536.
  • a certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 537.
  • a certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 538.
  • a certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 539.
  • a certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 540.
  • a certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 541.
  • a certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 542.
  • a certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 543.
  • a certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 544.
  • a certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 545.
  • a certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 546.
  • a certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 547.
  • a certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 548.
  • a certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 549.
  • a certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 550.
  • a certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 551.
  • a certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 552.
  • a certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 553.
  • a certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 554.
  • a certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 555.
  • a certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 556.
  • a certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 557.
  • a certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 558.
  • a certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 559.
  • a certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 560.
  • a certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 561.
  • a certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 562.
  • a certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 563.
  • a certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 564.
  • a certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 565.
  • a certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 566.
  • a certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 567.
  • a certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 568.
  • a certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 569.
  • a certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 570.
  • a certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 571.
  • a certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 572.
  • a certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 573.
  • a certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 574.
  • a certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 575.
  • a certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 576.
  • a certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 577.
  • a certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 578.
  • a certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 579.
  • a certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 580.
  • a certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 581.
  • a certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 582.
  • a certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 583.
  • a certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 584.
  • a certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 585.
  • a certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 586.
  • a certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 587.
  • a certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 588.
  • a certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 589.
  • a certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 590.
  • a certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 591.
  • a certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 592.
  • a certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 593.
  • a certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 594.
  • a certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 595.
  • a certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 596.
  • a certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 597.
  • a certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 598.
  • a certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 599.
  • a certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 600.
  • a certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 601.
  • a certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 602.
  • a certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 603.
  • a certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 604.
  • a certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 605.
  • a certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 606.
  • a certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 607.
  • a certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 608.
  • a certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 609.
  • a certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 610.
  • a certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 611.
  • a certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 612.
  • a certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 613.
  • a certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 614.
  • a certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 615.
  • a certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 616.
  • a certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 617.
  • a certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 618.
  • a certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 619.
  • a certain embodiment of present invention provides a method as described herein, wherein the level of an autoantibody recognizing p53 is measured.
  • a certain embodiment of present invention provides a method as described herein, wherein the level of an autoantibody in the blood sample of the human subject is 5 times higher than the level of said autoantibody representative for a human subject of a healthy population.
  • an autoantibody selected from the group of autoantibodies recognizing an human EGFR peptide as described herein, wherein the presence of said autoantibody is indicative for the presence of a mutation of exon 19 in the gene encoding EGFR in human tissue.
  • an autoantibody selected from the group of autoantibodies recognizing an human EGFR peptide as described herein, wherein the presence of said autoantibody is indicative for the presence of a deletion of exon 21 in the gene encoding EGFR in human tissue.
  • a certain embodiment of present invention provides erlotinib or a pharmaceutically acceptable salt thereof, in particular erlotinib hydrochloride, for use in treating a NSCLC patient identified by a method as described herein comprising administering erlotinib or a pharmaceutically acceptable salt thereof, in particular erlotinib hydrochloride to the patient.
  • a certain embodiment of present invention provides the use of an autoantibody for predicting the response of a NSCLC patient to erlotinib or a pharmaceutically acceptable salt thereof, in particular erlotinib hydrochloride, treatment, which antibody was identified by a method as described herein.
  • a certain embodiment of present invention provides a kit for detecting in a blood sample of the human subject a level of one or more autoantibodies selected from the group of autoantibodies recognizing human EGFR, wherein an increased level of said autoantibodies selected from the group of autoantibodies recognizing human EGFR in the blood sample of the human subject compared to a level of said autoantibodies representative for a human subject of a healthy population is indicative for non-small cell lung cancer.
  • a certain embodiment of present invention provides a kit according as described herein, wherein the autoantibody recognizes an EGFR peptide that is selected from Seq. Id. No. 1-Seq. Id. No. 15.
  • a certain embodiment of present invention provides a kit according as described herein, wherein the autoantibody recognizes an EGFR peptide that is selected from Seq. Id. No. 16-Seq. Id. No. 517.
  • a certain embodiment of present invention provides a kit according as described herein, wherein the autoantibody recognizes an EGFR peptide that is selected from Seq. Id. No. 518-Seq. Id. No. 602.
  • a certain embodiment of present invention provides a kit according as described herein, wherein the autoantibody recognizes an EGFR peptide that is selected from Seq. Id. No. 603-Seq. Id. No. 619.
  • a certain embodiment of present invention provides a kit according as described herein, wherein the autoantibody recognizes an EGFR peptide that is selected from Seq. Id. No. 519, Seq. Id. No. 520, Seq. Id. No. 521, and Seq. Id. No. 561.
  • FIG. 1 Log-transformed values of peptide binding for all peptides grouped by patient (49 samples, 4-digit numbers) and controls (1-digit numbers). Patients have on average higher signals, with a number of antibodies binding to peptides stronger than any signal in control sera.
  • FIG. 2 Histogram of distribution of the p-values for the significance of the antibody titers in a Cox regression model of OS or PFS ⁇ EGFR+TRT+EGFR:TRT+SEX+Antibody titer+ Antibody titer:TRT. If antibody titers do not affect survival, a uniform distribution is expected. The deviation from the uniform distribution is highly significant, which lead to the conclusion that approximately 50% of the 245 antibody titers with p-values ⁇ 0.05 will have a significant influence on progression free survival. A similar model calculation for overall survival (OS) yields 663 candidates at p-Values ⁇ 0.05 with a slightly better false discovery rate of approximately 40%.
  • OS overall survival
  • FIG. 3 Venn diagrams illustrating the refinement of peptide candidates for (A) progression free survival and (B) overall survival.
  • Peptide arrays were created by PepStarTM (JPT Peptide Technologies GmbH, Berlin, Germany) peptide microarray platform to generate customized peptide microarrays on glass slides for biomarker discovery, immunomonitoring and detection and validation of protein interactions. Peptides are immobilized on glass slides via a flexible linker. Chemoselective coupling generates microarrays of directed and covalently attached peptides.
  • 3661 specified native peptides with 500 scrambled control sequences covering the sequences of EGF-receptor, Arachidonate 15-lipoxygenase B (LX15B) and p53 and variants thereof were synthesized and arrays printed.
  • a serum dilution 1:200 was used for the detection of EGFR binding in NSCLC patient samples.
  • Incubation of microarrays was performed in an automated Hybridization Station HS4800 (Tecan) at 30° C. After washing, bound immunoglobine G (IgG) was detected with Cy5—labeled-anti-human secondary antibody (JIR, 0.1 ⁇ g/ml end-conc. in assay). Fluorescence was read using a Microarray Scanner GenePix with Autoloader 4200AL (Molecular Devices). Signal intensity is displayed as relative fluorescence units.
  • Blocking Solution SmartBlock Blocking Buffer Diluent for Serum and 2nd AB: SuperBlock T20 Blocking Buffer Wash Buffer 1: 1x TBS + 0.1% Tween 20 Wash Buffer 2: 0.1x SSC + 0.05% Tween 20
  • TASK was a 200-patient randomized, open label, Phase II study of Tarceva® in combination with Avastin® (bevazizumab) compared to standard chemotherapy regimens (gemcitabine plus cisplatin or paclitaxel plus carboplatin) plus Avastin® in first-line NSCLC patients. Further enrollment on this study was halt after data from a pre-planned interim analysis of the first 120 patients. Occurrence of rash was recorded as adverse event. Biopsies from all patients were tested for the occurrence of EGFR mutations and the mutation status has been recorded.
  • Clinical data accessible included outcome data, e.g. response overall survival and progression free survival as well as the rash grade and the mutation status of EGFR as measured from a pre-treatment biopsy.

Abstract

The invention generally relates to biomarkers associated with NSCLC, and methods and compositions for the detection and diagnosis of non-small cell lung cancer in a human subject.

Description

    RELATED APPLICATIONS
  • This application claims the benefit of EP Application No. 12171126.1, filed Jun. 7, 2012. All the teachings of the above-referenced application is incorporated herein by reference.
    • SEQUENCE LISTING
  • The instant application contains a Sequence Listing which has been submitted in ASCII format via EFS-Web and is hereby incorporated by reference in its entirety. Said ASCII copy, created on Jun. 3, 2013, is named P4928SeqList.txt and is 128,129 bytes in size.
    • FIELD OF THE INVENTION
  • The present invention provides methods for identifying patients diagnosed with non-small cell lung cancer who will most benefit from treatment with erlotinib comprising detecting autoantibodies in blood serum of said patients.
    • BACKGROUND OF THE INVENTION
  • Tarceva® is an orally active, potent, inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase (TKI).
  • Erlotinib hydrochloride is the active ingredient in Tarceva®, which is approved as single agent treatment for patients with advanced non-small cell lung cancer (NSCLC) after treatment with chemotherapy, as maintenance treatment for patients not progressing during chemotherapy (1st line maintenance) or after failure of chemotherapy (2nd/3rd line maintenance). Tarceva® is also approved as first line treatment for patients whose tumor harbors an EGFR activating mutation in the EU.
  • Expression of unusual proteins is common in cancer and viral infection. The mammalian immune system contains a specialized arm that recognizes proteins induced by cellular transformation (neo-antigens) and effectively eliminates cells that express these neo-antigens against which tolerance has not established during development. This arm of the immune system is thought to be effective against viral infections, spontaneous chromosomal and genomic rearrangements caused by errors of the cell division machinery, or carcinogen-induced transforming mutations. While the initial cytotoxic immune response—which is mediated by the recognition of the unusual proteins displayed on MHCI complexes by CD8+ T-cells—is fast and effective, a sustained response against virus infections or aberrant cellular clones requires the co-stimulatory effect of CD4+ T-helper cells which are activated after presentation of extracellular peptides (which can stem from cells lysed in the first phase of the cytotoxic immune response) via MHCII complexes of professional antigen presenting cells. Additionally, these cells are able to induce a lasting B-cell response and antibodies to viral or aberrant proteins. The infiltration of a tumor with large numbers of CD8+ T-cells has shown to be a better prognostic marker than traditional tumor staging in colorectal cancer (Koizumi, Hojo et al. 20071), and it has been associated with favorable prognosis in almost all major solid carcinomas independently of cancer cell type. 1Koizumi, K., S. Hojo, et al. (2007). “Chemokine receptors in cancer metastasis and cancer cell-derived chemokines in host immune response.” Cancer Science 98(11): 1652-1658
  • Autoantibodies are well known diagnostic entities in cancer. Many cancer autoantibodies are proteins that are normally expressed in embryonic tissues and therefore represent a “foreign” protein against which immune tolerance is not established. The shedding of these proteins to the bloodstream late in cancer history leads to a humoral immune response. A typical example is the common cancer marker CEA (cancer embryonic antigen). Tumors frequently exhibit faulty protein processing. Prominent examples include proteins that are incorrectly cleaved by cell localization proteases (the presence of autoantibodies against the N-terminal sequence of p53 which is normally cleaved after the protein is targeted to the nucleus is one of the most specific biomarkers of lung cancer) or incorrectly glycosylated by cellular glycosylases (anti-MUC1-antibodies against a form of MUC1 that is incorrectly O-glycosylated is a biomarker for a variety of cancers). Even though p53 mutations are frequently observed in tumors, the specificity of the autoantibodies against this protein is almost always against the N-terminus of the protein—connecting the immunogenicity of p53 more to the ectopic expression of a protein that is normally short lived and located in the nucleus.
  • The detection of natural EGFR autoantibodies in serum of NSCLC patients has been described by Li et al.2. Li et al.3 and Chapman et al.4 described the detection of natural autoantibodies to p53, HER2, NY-ESO-1, CAGE, MUC1 and GBU4-5. Further, WO20110739055 relates to tumor markers associated with the progression of a cancer disease from a less progressed stage to a more progressed stage. 2Li Yuan et al, Chinese Journal of Lung Cancer, 13(7), 2010, 727-7303Li Yuan et al, Chinese Journal of Lung Cancer, 12(10), 2009, 1999-61874C J Chapman, A Murray, J E McElveen, U Sahin, U Luxemburger, Ö Türeci, R Wiewrodt, A C Barnes, J F Robertson, “Autoantibodies in lung cancer: possibilities for early detection and subsequent cure”, Thorax 2008; 63(3):228-2335WO2011073905
  • Unusual (mutated or expressed in abnormal quantities or locations) tumor proteins can invoke an antibody response. Tumor-induced autoantibodies have frequently been observed and their utility as diagnostic markers has been investigated (Albert and Darnell 20046). While autoantibodies to tumor proteins can be found that have exquisite specificity, most of them lack the required sensitivity for a diagnostic test. 6Albert, M. L. and R. B. Darnell (2004). “Paraneoplastic neurological degenerations: Keys to tumor immunity.” Nat. Rev. Cancer 4(1): 36-44
  • Few reliable epidemiologic and genetic markers that predict erlotinib hydrochloride response are known in the art. In particular, EGFR mutations in exon 18-21 (intracellular kinase domain of the receptor) were described to be linked with better prognosis as well as with better response to TKI treatment (Paz-Ares, Soulieres et al. 20107). The only predictive marker currently known (EGFR activating mutation) is difficult to diagnose as a biopsy of the tumor is needed. At present only about 50% of NSCLC patients are diagnosed with a biopsy (Reck, Hermes et al. 20118). There is a definite need for simpler techniques to detect predictive markers of TKI efficacy. It is desirable to identify the responders at diagnosis in order to have as many patients as possible benefiting from erlotinib treatment as early as possible, while exploring other treatment options for patients not likely to respond. 7Paz-Ares, L., D. Soulieres, et al. (2010). “Clinical outcomes in non-small-cell lung cancer patients with EGFR mutations: pooled analysis.” J Cell Mol Med 14(1-2): 51-698Reck, M., A. Hermes, et al. (2011). “Tissue sampling in lung cancer: A review in light of the MERIT experience.” Lung Cancer 74(1): 1-6
    • DETAILED DESCRIPTION OF THE INVENTION
  • Present invention solves that problem in that it provides a method of diagnosis of cancer in a human subject.
  • Present invention solves that problem in that it provides a method of diagnosis of non-small cell lung cancer in a human subject.
  • Present invention solves that problem in that it provides a method of diagnosis of non-small cell lung cancer in a human subject by providing antibodies against mutated EGFR sequences.
  • A patient identified by a method as described herein is a patient, in particular a NSCLC patient who will respond to the treatment with erlotinib or a pharmaceutically acceptable salt thereof, in particular erlotinib hydrochloride.
  • We surprisingly found that present autoantibodies possess the required sensitivity for a diagnostic test, especially autoantibodies against mutated EGFR sequences.
  • EGFR is normally bound to the cell membrane and not shed to the bloodstream. EGFR is a normal adult protein that is found in large quantities in some adult tissues. Immune tolerance is expected to be established against this protein and many of its variants. Almost all of the sequences belong to the cytoplasmic part of the molecule and are invisible to professional antigen presenting cells. The mutations affect only a small part of the EGFR molecule.
  • Unless defined otherwise, all terms used herein have the same meanings as commonly understood by a skilled artisan to which art this invention belongs.
  • The term “a level of said autoantibody representative for a human subject of a healthy population” refers to an estimate of the mean level of the autoantibody in serum of a population of patients who do not suffer from NSCLC.
  • The term “a level of said autoantibody representative for a NSCLC patient” refers to an estimate of the mean level of the autoantibody in serum of a population of patients who suffer from NSCLC.
  • The term “overall survival (OS)” refers to the length of time from diagnosis of disease during and after treatment the patient survives. As the skilled person will appreciate, a patient's overall survival is improved or enhanced, if the patient belongs to a subgroup of patients that has a statistically significant longer mean survival time as compared to another subgroup of patients.
  • The term “progression-free survival (PFS)” refers to the length of time from diagnosis of disease during and after treatment during which, according to the assessment of the treating physician or investigator, the patient's disease does not become worse, i.e., does not progress. As the skilled person will appreciate, a patient's progression-free survival is improved or enhanced if the patient belongs to a subgroup of patients that has a longer length of time during which the disease does not progress as compared to the average or mean progression free survival time of a control group of similarly situated patients.
  • The term “patient” refers to any single mammal for which treatment is desired. In particular, the “patient” is a human subject. More particularly, the patient is a human subject suffering from cancer, in particular NSCLC.
  • The term “autoantibody” is a type of protein manufactured by the immune system of a patient that is directed against one or more of the patient's own proteins.
  • The term “amino acid” denotes the group of naturally occurring carboxy a-amino acids comprising alanine (three letter code: ala, one letter code: A), arginine (arg, R), asparagine (asn, N), aspartic acid (asp, D), cysteine (cys, C), glutamine (gln, Q), glutamic acid (glu, E), glycine (gly, G), histidine (his, H), isoleucine (ile, I), leucine (leu, L), lysine (lys, K), methionine (met, M), phenylalanine (phe, F), proline (pro, P), serine (ser, S), threonine (thr, T), tryptophan (trp, W), tyrosine (tyr, Y), and valine (val, V).
  • As used herein, “therapy” or “treatment” (and grammatical variations thereof such as “treat” or “treating”) refers to clinical intervention in an attempt to alter the natural course of a disease in the individual being treated, and can be performed either for prophylaxis or during the course of clinical pathology. Desirable effects of treatment include, but are not limited to, preventing occurrence or recurrence of disease, alleviation of symptoms, diminishment of any direct or indirect pathological consequences of the disease, preventing metastasis, decreasing the rate of disease progression, amelioration or palliation of the disease state, and remission or improved prognosis.
  • The term “gene” as used herein comprises variants of the gene. The term “variant” relates to nucleic acid sequences which are substantially similar to the nucleic acid sequences given by the GenBank accession number. The term “substantially similar” is well understood by a person skilled in the art. In particular, a gene variant may be an allele which shows nucleotide exchanges compared to the nucleic acid sequence of the most prevalent allele in the human population. Preferably, such a substantially similar nucleic acid sequence has a sequence similarity to the most prevalent allele of at least 80%, preferably at least 85%, more preferably at least 90%, most preferably at least 95%. The term “variants” is also meant to relate to splice variants.
  • The term “mutation” refers to changes in a genomic sequence. These random sequences can be defined as sudden and spontaneous changes in the cell. Mutation can result in several different types of change in sequences; these can either have no effect, alter the product of a gene, or prevent the gene from functioning properly or completely. The term “somatic mutation” refers to a change in the genetic structure that is neither inherited nor passed to offspring.
  • The phrase “recommending a treatment” as used herein refers to using the information or data generated relating to the level or presence of a biomarker or an autoantibody in a sample of a patient to identify the patient as suitably treated or not suitably treated with a therapy. In some embodiment the therapy may comprise a drug. The information or data may be in any form, written, oral or electronic. In some embodiments, using the information or data generated includes communicating, presenting, reporting, storing, sending, transferring, supplying, transmitting, delivering, dispensing, or combinations thereof. In some embodiments, communicating, presenting, reporting, storing, sending, transferring, supplying, transmitting, delivering, dispensing, or combinations thereof are performed by a computing device, analyzer unit or combination thereof. In some further embodiments, communicating, presenting, reporting, storing, sending, transferring, supplying, transmitting, delivering, dispensing, or combinations thereof are performed by a laboratory or medical professional. In some embodiments, the information or data includes a comparison of the level of said biomarker or autoantibody to a reference level. In some embodiments, the information or data includes an indication that said biomarker or autoantibody is present or absent in the sample. In some embodiments, the information or data includes an indication that the patient is suitably treated or not suitably treated with a therapy comprising said drug. In some embodiments, the therapy is erlotinib.
  • The phrase “providing a diagnosis” as used herein refers to using the information or data generated relating to the level or presence of a biomarker or an autoantibody in a sample of a patient to diagnose a disease in the patent. The information or data may be in any form, written, oral or electronic. In some embodiments, using the information or data generated includes presenting, reporting, storing, sending, transferring, supplying, transmitting, delivering, dispensing, or combinations thereof. In some embodiments, presenting, reporting, storing, sending, transferring, supplying, transmitting, delivering, dispensing, or combinations thereof are performed by a computing device, analyzer unit or combination thereof. In some embodiments, presenting, reporting, storing, sending, transferring, supplying, transmitting, delivering, dispensing, or combinations thereof are performed by a laboratory or medical professional. In some embodiments, the information or data includes a comparison of the level of said biomarker or autoantibody to a reference level. In some embodiments, the information or data includes an indication that said biomarker or autoantibody is present or absent in the sample. In some embodiments, the information or data includes an indication that the patient is diagnosed with said disease. In some embodiments, said disease is non-small cell lung cancer.
  • During the TASK study, biopsy material had been collected and the tumor cells have been tested for the presence of the most frequent somatic mutations, i.e. a deletion at exon 19, and a point mutation at exon 21. During the TASK study serum samples had been collected at various time points (pre-dose, day 8, day 22 and progression) from all patients and were assessed for autoantibodies against EGFR.
  • In these patients, autoantigenic peptide sequences that predict development of rash, or prolonged progression free or overall survival inevitably include a set of sequences that are derived from the EGFR sequence starting at position 737 and extending through 756. These peptides include a number of sequence variants, but inevitably include sequences that have a deletion at position 746-750 or close nearby (Table 2).
  • This corresponds exactly to the position of the deletion in the exon 19 somatic mutation, known to be predictive for outstanding efficacy from treatment with TKI (Rosell et al. 20099, Mok et al. 200910). 9Rosell et al., N Engl J Med 2009; 361:958-96710Mok et al., N Engl J Med 2009; 361:947-957
  • The presence of a somatic EGFR mutation in exon 19 in tumor tissue leads to protein variant against that the immune system has not developed tolerance. The somatic mutation occurs only in the tumor, and therefore, if it induces an autoantibody which can be detected in the patient's serum it can be used to draw conclusions about the presence of an exon 19 mutation or exon 21 mutation in the NSCLC tissue, which is well known to predict increased progression free survival and superiority of tyrosine kinase monotherapy over chemotherapy (Heigener and Reck 201111). 11Heigener, D. and M. Reck (2011). “Mutations in the epidermal growth factor receptor gene in non-small cell lung cancer: Impact on treatment beyond gefitinib and erlotinib.” Advances in Therapy 28(2): 126-133
  • The autoantibody can be detected using a standard blood sample from the patient without the need to obtain tumor cells with a biopsy. This is a large advantage over the current practice, as recovery rates of useful tumor samples even in clinical studies do not exceed 50% (Reck, Hermes et al. 201112). 12Reck, M., A. Hermes, et al. (2011). “Tissue sampling in lung cancer: A review in light of the MERIT experience.” Lung Cancer 74(1): 1-6
  • Anti-EGFR autoantibodies can be detected in blood samples of NSCLC patients at higher concentrations than in healthy controls (FIG. 1). In particular, peptide sequences have been identified that yield consecutive regions of high immunogenicity with large differences between patient and healthy controls sera. Consecutive sequence stretches were identified, where ratios of individual peptide signals in more than 30% of the cancer patients to maximum value in controls was larger than 8 (Table 1).
  • TABLE 1 
    Consecutive EGFR sequences with high
    autoantigenicity in NLSCL patients
    Consensus sequence of
    Sequence autoantigenic
    Protein Region peptides in the region
    EGFR 323-336 VRKSKKSEGPSxKV
    EGFR 546-564 PREFVENSECIQCHPECL
    EGFR 574-591 RGPDNCIQCAHYIDGPHCVKTCP
    EGFR 735-762 GEKVKIPVAIK[-S]PKANK
    Del
     1
    EGFR 739-758 KIPVAIK[-HRK]PTSPK
    Del
     2
    EGFR 793-806 MPFGCLLDYVREH
    EGFR 867-883 KEYHAEGGKVPIKWM
    EGFR  986-1002 RMHLPSPTDSNFYRA
    EGFR 1081-1095 SIDDTFLPVPEYIN
    EGFR 1148-1166 NSTFDSPAHWAQKGSHQI
  • The above sequences can be used for the early diagnosis of NSCLC.
  • Regression analysis has identified significant evidence that the presence of antibodies to the peptides influence both, progression free survival (PFS) and overall survival (OS) (FIG. 2). Although the number of samples is small in comparison to the number of peptides, many covariates need to be considered and none of the individual peptides reach sufficient statistical significance, we surprisingly found that when combining overlapping information from various independent statistical approaches, selection of a relevant peptide from the many candidates obtained after univariate analysis is possible. FIG. 3 illustrates the process that led to selection of the candidate sequences listed in Table 2. Sequences listed in Table 2 or any continuous subsequences thereof longer than 8 amino acids are candidate sequences.
  • TABLE 2 
    Antigenic sequences influencing PFS and OS of NSCLC patients
    Consensus sequence of
    Sequence autoantigenic
    Protein Region peptides in the region Source
    EGFR 737-756 KVKIPVAIKELREATSPKA PFS ~ Peptide and
    EGFR 737-756 Del  KVKIPVAIK------[SA]PKA treatment in EGFR -
    742-748 mutation positive
    patients with rash
    EGFR 763-776 A[YV]VMASVDNPHVCR Consensus of
    EGFR 703-717 LLRILKETE[FS]KKI statistical
    EGFR 825-838 MNYLEDR[RL]LVHRD analyses for PFS
    EGFR 296-309 KGNYVVTDHGSCVRA Consensus of
    EGFR 628-641 CTGPGLEGCPTNG statistical
    EGFR 681-727 RLLQEREL[VL]EPLTPSGEAPNQA[L analyses for OS
    PF]LR[IT]L[KM]ETE[FL]KK[IL]
    [KF]VLG[SP]GAFGT
    EGFR 761-780 DEAYVMASVDNPHVCRLLG
    EGFR 830-843 YLEDRRLVHRDLA
  • TABLE 3 
    Examples for peptide sequences with high
    predictive potential for prolonged
    progression free survival in patients with 
    EGFR mutations that develop rash
    KVKIPVAIKELREATSPKA Annotation
    KVKIPVAIK------APKA 737_V003
    KVKIPVAIK---APTS 737_V004
    KVKIPVAIKD------PKA 737_V007
    KVKIPVAIKELKA 737_V015
    KVKIPVAIKE------PKA 737_V019
    KVKIPVAIKEQKA 737_V024
    KVKIPVAIKESKA 737_V029
    KVKIPVAIKEV-----PK 737_V037
    KVKIPVAIK------IPKA 737_V039
    KVKIPVAIK------SPKA 737_V054
    KVKIPVAIK------TPKA 737_V057
    --KIPVAIKE----ASPKA 739 V010
    --KIPVAIKEF----SPKA 739_V013
    --KIPVAIKE----NSPKA 739_V027
    --KIPVAIK----VASPKA 739_V067
    --KIPVAIK----VPSPKA 739_V070
  • EGFR peptide sequences selected from Seq. Id. No. 1-Seq. Id. No. 15 are consecutive sequences with high autoantigenicity in NLSCL patients.
  • EGFR peptide sequences selected from Seq. Id. No. 16-Seq. Id. No. 517 are useful for predicting the occurrence and grade of adverse events like rash to erlotinib treatment.
  • EGFR peptide sequences selected from Seq. Id. No. 518-Seq. Id. No. 602 are antigenic sequences influencing, in particular extending, progression free and overall survival of NSCLC patients, in particular mutated EGFR peptide sequences Seq. Id. No. 554, Seq. Id. No. 555, Seq. Id. No. 556, Seq. Id. No. 557, Seq. Id. No. 558, Seq. Id. No. 559 and Seq. Id. No. 560, as well as EGFR peptide sequences Seq. Id. No. 519, Seq. Id. No. 520, Seq. Id. No. 521 and Seq. Id. No. 561.
  • EGFR peptide sequences selected from Seq. Id. No. 603-Seq. Id. No. 619 have high predictive potential for prolonged progression free survival in patients with EGFR mutations that develop rash.
  • Antibodies against these peptide sequences most likely influence PFS and OS if they are present in patients. Tests that detect the presence of these antibodies in patient sera could be used to guide treatment and stratify patients into treatment groups.
  • Present invention provides a method of diagnosis of non-small cell lung cancer in a human subject comprising:
  • measuring in a blood sample of the human subject a level of an autoantibody selected from the group of autoantibodies recognizing mutated human EGFR, wherein an increased level of said autoantibody selected from the group of autoantibodies recognizing mutated human EGFR in the blood sample of the human subject compared to a level of said autoantibody representative for a human subject of a healthy population is indicative for non-small cell lung cancer.
  • Present invention provides a method of diagnosis of non-small cell lung cancer in a human subject comprising:
  • a) measuring in a blood sample of the human subject a level of an autoantibody selected from the group of autoantibodies recognizing mutated human EGFR,
  • b) comparing the level of said autoantibody to a reference level, and
  • c) providing a diagnosis of non-small cell lung cancer when the level of said autoantibody is above the reference level.
  • Present invention provides a method of diagnosis of non-small cell lung cancer in a human subject comprising:
  • a) measuring in a blood sample of the human subject a level of an autoantibody selected from the group of autoantibodies recognizing mutated human EGFR,
  • b) comparing the level of said autoantibody to a reference level, and
  • c) recommending a treatment when the level of said autoantibody is above the reference level.
  • A certain embodiment of the present invention provides a method as described above, wherein said treatment is erlotinib.
  • A certain embodiment of present invention provides a method as described herein, wherein the level of an autoantibody recognizing mutated human EGFR is measured.
  • A certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes a mutated EGFR peptide is selected from the group consisting of Seq. Id. No. 1, Seq. Id. No. 2, Seq. Id. No. 4, Seq. Id. No. 5, Seq. Id. No. 6, Seq. Id. No. 7, Seq. Id. No. 15, Seq. Id. No. 16, Seq. Id. No. 17, Seq. Id. No. 18, Seq. Id. No. 19, Seq. Id. No. 20, Seq. Id. No. 21, Seq. Id. No. 22, Seq. Id. No. 23, Seq. Id. No. 24, Seq. Id. No. 25, Seq. Id. No. 26, Seq. Id. No. 27, Seq. Id. No. 28, Seq. Id. No. 29, Seq. Id. No. 30, Seq. Id. No. 31, Seq. Id. No. 32, Seq. Id. No. 33, Seq. Id. No. 34, Seq. Id. No. 35, Seq. Id. No. 36, Seq. Id. No. 37, Seq. Id. No. 38, Seq. Id. No. 39, Seq. Id. No. 40, Seq. Id. No. 41, Seq. Id. No. 42, Seq. Id. No. 43, Seq. Id. No. 44, Seq. Id. No. 45, Seq. Id. No. 46, Seq. Id. No. 47, Seq. Id. No. 48, Seq. Id. No. 49, Seq. Id. No. 50, Seq. Id. No. 51, Seq. Id. No. 52, Seq. Id. No. 53, Seq. Id. No. 54, Seq. Id. No. 55, Seq. Id. No. 56, Seq. 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  • A certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes a mutated EGFR peptide that is selected from the groups consisting of Seq. Id. No. 1, Seq. Id. No. 2, Seq. Id. No. 4, Seq. Id. No. 5, Seq. Id. No. 6, Seq. Id. No. 7 and Seq. Id. No. 15.
  • A certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes a mutated EGFR peptide that is selected from the group consisting of Seq. Id. No. 16, Seq. Id. No. 17, Seq. Id. No. 18, Seq. Id. No. 19, Seq. Id. No. 20, Seq. Id. No. 21, Seq. Id. No. 22, Seq. Id. No. 23, Seq. Id. No. 24, Seq. Id. No. 25, Seq. Id. No. 26, Seq. Id. No. 27, Seq. Id. No. 28, Seq. Id. No. 29, Seq. Id. No. 30, Seq. Id. No. 31, Seq. Id. No. 32, Seq.
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  • A certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes a mutated EGFR peptide that is selected from the group consisting of Seq. Id. No. 518, Seq. Id. No. 522, Seq. Id. No. 523, Seq. Id. No. 524, Seq. Id. No. 526, Seq. Id. No. 527, Seq. Id. No. 528, Seq. Id. No. 529, Seq. Id. No. 530, Seq. Id. No. 531, Seq. Id. No. 532, Seq. Id. No. 533, Seq. Id. No. 534, Seq. Id. No. 535, Seq. Id. No. 536, Seq. Id. No. 537, Seq. Id. No. 538, Seq. Id. No. 539, Seq. Id. No. 540, Seq. Id. No. 541, Seq. Id. No. 542, Seq. Id. No. 543, Seq. Id. No. 544, Seq. Id. No. 545, Seq. Id. No. 546, Seq. Id. No. 547, Seq. Id. No. 548, Seq. Id. No. 549, Seq. Id. No. 550, Seq. Id. No. 551, Seq. Id. No. 552, Seq. Id. No. 553, Seq. Id. No. 554, Seq. Id. No. 555, Seq. Id. No. 557, Seq. Id. No. 559, Seq. Id. No. 560, Seq. Id. No. 562, Seq. Id. No. 563, Seq. Id. No. 564, Seq. Id. No. 565, Seq. Id. No. 567, Seq. Id. No. 568, Seq. Id. No. 569, Seq. Id. No. 570, Seq. Id. No. 571, Seq. Id. No. 572, Seq. Id. No. 573, Seq. Id. No. 574, Seq. Id. No. 575, Seq. Id. No. 576, Seq. Id. No. 577, Seq. Id. No. 578, Seq. Id. No. 579, Seq. Id. No. 580, Seq. Id. No. 581, Seq. Id. No. 582, Seq. Id. No. 583, Seq. Id. No. 584, Seq. Id. No. 585, Seq. Id. No. 586, Seq. Id. No. 587, Seq. Id. No. 588, Seq. Id. No. 589, Seq. Id. No. 590, Seq. Id. No. 591, Seq. Id. No. 592, Seq. Id. No. 593, Seq. Id. No. 594, Seq. Id. No. 595, Seq. Id. No. 596, Seq. Id. No. 597, Seq. Id. No. 598, Seq. Id. No. 599 and Seq. Id. No. 601.
  • A certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes a mutated EGFR peptide that is selected from the group consisting of Seq. Id. No. 604, Seq. Id. No. 605, Seq. Id. No. 606, Seq. Id. No. 607, Seq. Id. No. 608, Seq. Id. No. 609, Seq. Id. No. 610, Seq. Id. No. 611, Seq. Id. No. 612, Seq. Id. No. 613, Seq. Id. No. 614, Seq. Id. No. 615, Seq. Id. No. 616, Seq. Id. No. 617, Seq. Id. No. 618 and Seq. Id. No. 619.
  • A certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide that is selected from the group consisting of Seq. Id. No. 519, Seq. Id. No. 520, Seq. Id. No. 521, and Seq. Id. No. 561.
  • A certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes a mutated EGFR peptide that is selected from the group consisting of Seq. Id. No. 554, Seq. Id. No. 555, Seq. Id. No. 556, Seq. Id. No. 557, Seq. Id. No. 558, Seq. Id. No. 559, and Seq. Id. No. 560.
  • A certain embodiment of present invention provides a method as described herein, wherein the level of an autoantibody in the blood sample of the human subject is 5 times higher than the level of said autoantibody representative for a human subject of a healthy population.
  • A certain embodiment of present invention provides erlotinib or a pharmaceutically acceptable salt thereof, in particular erlotinib hydrochloride, for use in treating a NSCLC patient identified by a method as described herein comprising administering erlotinib or a pharmaceutically acceptable salt thereof, in particular erlotinib hydrochloride to the patient.
  • A certain embodiment of present invention provides the use of an autoantibody for predicting the response of a NSCLC patient to erlotinib or a pharmaceutically acceptable salt thereof, in particular erlotinib hydrochloride, treatment, which antibody was identified by a method as described herein.
  • A certain embodiment of present invention provides a kit for detecting in a blood sample of the human subject a level of one or more autoantibodies selected from the group of autoantibodies recognizing mutated human EGFR, wherein an increased level of said autoantibodies selected from the group of autoantibodies recognizing mutated human EGFR in the blood sample of the human subject compared to a level of said autoantibodies representative for a human subject of a healthy population is indicative for non-small cell lung cancer.
  • A certain embodiment of present invention provides a kit as described herein, wherein the autoantibody recognizes a mutated EGFR peptide that is selected from the group consisting of Seq. Id. No. 1, Seq. Id. No. 2, Seq. Id. No. 4, Seq. Id. No. 5, Seq. Id. No. 6, Seq. Id. No. 7 and Seq. Id. No. 15.
  • A certain embodiment of present invention provides a kit as described herein, wherein the autoantibody recognizes a mutated EGFR peptide that is selected from the group consisting of Seq. Id. No. 16, Seq. Id. No. 17, Seq. Id. No. 18, Seq. Id. No. 19, Seq. Id. No. 20, Seq. Id. No. 21, Seq. Id. No. 22, Seq. Id. No. 23, Seq. Id. No. 24, Seq. Id. No. 25, Seq. Id. No. 26, Seq. Id. No. 27, Seq. Id. No. 28, Seq. Id. No. 29, Seq. Id. No. 30, Seq. Id. No. 31, Seq. Id. No. 32, Seq. Id. No. 33, Seq. Id. No. 34, Seq. Id. No. 35, Seq. Id. No. 36, Seq. Id. No. 37, Seq. Id. No. 38, Seq. Id. No. 39, Seq. Id. No. 40, Seq. Id. No. 41, Seq. Id. No. 42, Seq. Id. No. 43, Seq. Id. No. 44, Seq. Id. No. 45, Seq. Id. No. 46, Seq. Id. No. 47, Seq. Id. No. 48, Seq. Id. No. 49, Seq. Id. No. 50, Seq. Id. No. 51, Seq. Id. No. 52, Seq. Id. No. 53, Seq. Id. No. 54, Seq. Id. No. 55, Seq. Id. No. 56, Seq. Id. No. 57, Seq. Id. No. 58, Seq. Id. No. 59, Seq. Id. No. 60, Seq. Id. No. 61, Seq. Id. No. 62, Seq. Id. 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  • A certain embodiment of present invention provides a kit as described herein, wherein the autoantibody recognizes a mutated EGFR peptide that is selected from the group consisting of Seq. Id. No. 518, Seq. Id. No. 522, Seq. Id. No. 523, Seq. Id. No. 524, Seq. Id. No. 526, Seq. Id. No. 527, Seq. Id. No. 528, Seq. Id. No. 529, Seq. Id. No. 530, Seq. Id. No. 531, Seq. Id. No. 532, Seq. Id. No. 533, Seq. Id. No. 534, Seq. Id. No. 535, Seq. Id. No. 536, Seq. Id. No. 537, Seq. Id. No. 538, Seq. Id. No. 539, Seq. Id. No. 540, Seq. Id. No. 541, Seq. Id. No. 542, Seq. Id. No. 543, Seq. Id. No. 544, Seq. Id. No. 545, Seq. Id. No. 546, Seq. Id. No. 547, Seq. Id. No. 548, Seq. Id. No. 549, Seq. Id. No. 550, Seq. Id. No. 551, Seq. Id. No. 552, Seq. Id. No. 553, Seq. Id. No. 554, Seq. Id. No. 555, Seq. Id. No. 557, Seq. Id. No. 559, Seq. Id. No. 560, Seq. Id. No. 562, Seq. Id. No. 563, Seq. Id. No. 564, Seq. Id. No. 565, Seq. Id. No. 567, Seq. Id. No. 568, Seq. Id. No. 569, Seq. Id. No. 570, Seq. Id. No. 571, Seq. Id. No. 572, Seq. Id. No. 573, Seq. Id. No. 574, Seq. Id. No. 575, Seq. Id. No. 576, Seq. Id. No. 577, Seq. Id. No. 578, Seq. Id. No. 579, Seq. Id. No. 580, Seq. Id. No. 581, Seq. Id. No. 582, Seq. Id. No. 583, Seq. Id. No. 584, Seq. Id. No. 585, Seq. Id. No. 586, Seq. Id. No. 587, Seq. Id. No. 588, Seq. Id. No. 589, Seq. Id. No. 590, Seq. Id. No. 591, Seq. Id. No. 592, Seq. Id. No. 593, Seq. Id. No. 594, Seq. Id. No. 595, Seq. Id. No. 596, Seq. Id. No. 597, Seq. Id. No. 598, Seq. Id. No. 599 and Seq. Id. No. 601.
  • A certain embodiment of present invention provides a kit as described herein, wherein the autoantibody recognizes a mutated EGFR peptide that is selected from the group consisting of Seq. Id. No. 604, Seq. Id. No. 605, Seq. Id. No. 606, Seq. Id. No. 607, Seq. Id. No. 608, Seq. Id. No. 609, Seq. Id. No. 610, Seq. Id. No. 611, Seq. Id. No. 612, Seq. Id. No. 613, Seq. Id. No. 614, Seq. Id. No. 615, Seq. Id. No. 616, Seq. Id. No. 617, Seq. Id. No. 618 and Seq. Id. No. 619.
  • A certain embodiment of present invention provides a kit as described herein, wherein the autoantibody recognizes a mutated EGFR peptide that is selected from the group consisting of Seq. Id. No. 554, Seq. Id. No. 555, Seq. Id. No. 556, Seq. Id. No. 557, Seq. Id. No. 558, Seq. Id. No. 559, and Seq. Id. No. 560.
  • A certain embodiment of present invention provides a kit as described herein, wherein the autoantibody recognizes an EGFR peptide that is selected from the group consisting of Seq. Id. No. 519, Seq. Id. No. 520, Seq. Id. No. 521, and Seq. Id. No. 561.
  • A certain embodiment of present invention provides a method of diagnosis of non-small cell lung cancer in a human subject comprising:
  • measuring in a blood sample of the human subject a level of an autoantibody selected from the group of autoantibodies recognizing human EGFR, wherein an increased level of said autoantibody selected from the group of autoantibodies recognizing human EGFR in the blood sample of the human subject compared to a level of said autoantibody representative for a human subject of a healthy population is indicative for non-small cell lung cancer, in particular wherein the level of an autoantibody recognizing human EGFR is measured.
  • Present invention provides a method of diagnosis of non-small cell lung cancer in a human subject comprising:
  • a) measuring in a blood sample of the human subject a level of an autoantibody selected from the group of autoantibodies recognizing human EGFR,
  • b) comparing the level of said autoantibody to a reference level, and
  • c) providing a diagnosis of non-small cell lung cancer when the level of said autoantibody is above the reference level.
  • Present invention provides a method of diagnosis of non-small cell lung cancer in a human subject comprising:
  • a) measuring in a blood sample of the human subject a level of an autoantibody selected from the group of autoantibodies recognizing mutated human EGFR,
  • b) comparing the level of said autoantibody to a reference level, and
  • c) recommending a treatment when the level of said autoantibody is above the reference level.
  • A certain embodiment of the present invention provides a method as described above, wherein said treatment is erlotinib.
  • A certain embodiment of present invention provides a method as described above, wherein the autoantibody recognizes an EGFR peptide is selected from the group consisting of Seq. Id. No. 1, Seq. Id. No. 2, Seq. Id. No. 3, Seq. Id. No. 4, Seq. Id. No. 5, Seq. Id. No. 6, Seq. Id. No. 7, Seq. Id. No. 8, Seq. Id. No. 9, Seq. Id. No. 10, Seq. Id. No. 11, Seq. Id. No. 12, Seq. Id. No. 13, Seq. Id. No. 14, Seq. Id. No. 15, Seq. Id. No. 16, Seq. Id. No. 17, Seq. Id. No. 18, Seq. Id. No. 19, Seq. Id. No. 20, Seq. Id. No. 21, Seq. Id. No. 22, Seq. Id. No. 23, Seq. Id. No. 24, Seq. Id. No. 25, Seq. Id. No. 26, Seq. Id. No. 27, Seq. Id. No. 28, Seq. Id. No. 29, Seq. Id. No. 30, Seq. Id. No. 31, Seq. Id. No. 32, Seq. Id. No. 33, Seq. Id. No. 34, Seq. Id. No. 35, Seq. Id. No. 36, Seq. Id. No. 37, Seq. Id. No. 38, Seq. Id. No. 39, Seq. Id. No. 40, Seq. Id. No. 41, Seq. Id. No. 42, Seq. Id. No. 43, Seq. Id. No. 44, Seq. Id. No. 45, Seq. Id. No. 46, Seq. Id. No. 47, Seq. Id. No. 48, Seq. Id. No. 49, Seq. Id. No. 50, Seq. Id. No. 51, Seq. Id. No. 52, Seq. Id. No. 53, Seq. Id. No. 54, Seq. Id. No. 55, Seq. Id. No. 56, Seq. Id. No. 57, Seq. Id. No. 58, Seq. Id. No. 59, Seq. Id. No. 60, Seq. Id. No. 61, Seq. Id. No. 62, Seq. Id. No. 63, Seq. Id. No. 64, Seq. Id. No. 65, Seq. Id. No. 66, Seq. Id. No. 67, Seq. Id. No. 68, Seq. Id. No. 69, Seq. Id. No. 70, Seq. Id. No. 71, Seq. Id. No. 72, Seq. Id. No. 73, Seq. Id. No. 74, Seq. Id. No. 75, Seq. Id. No. 76, Seq.
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No. 408, Seq. Id. No. 409, Seq. Id. No. 410, Seq. Id. No. 411, Seq. Id. No. 412, Seq. Id. No. 413, Seq. Id. No. 414, Seq. Id. No. 415, Seq. Id. No. 416, Seq. Id. No. 417, Seq. Id. No. 418, Seq. Id. No. 419, Seq. Id. No. 420, Seq. Id. No. 421, Seq. Id. No. 422, Seq. Id. No. 423, Seq. Id. No. 424, Seq. Id. No. 425, Seq. Id. No. 426, Seq. Id. No. 427, Seq. Id. No. 428, Seq. Id. No. 429, Seq. Id. No. 430, Seq. Id. No. 431, Seq. Id. No. 432, Seq. Id. No. 433, Seq. Id. No. 434, Seq. Id. No. 435, Seq. Id. No. 436, Seq. Id. No. 437, Seq. Id. No. 438, Seq. Id. No. 439, Seq. Id. No. 440, Seq. Id. No. 441, Seq. Id. No. 442, Seq. Id. No. 443, Seq. Id. No. 444, Seq. Id. No. 445, Seq. Id. No. 446, Seq. Id. No. 447, Seq. Id. No. 448, Seq. Id. No. 449, Seq. Id. No. 450, Seq. Id. No. 451, Seq. Id. No. 452, Seq. Id. No. 453, Seq. Id. No. 454, Seq. Id. No. 455, Seq. Id. No. 456, Seq. Id. No. 457, Seq. Id. No. 458, Seq. Id. No. 459, Seq. Id. No. 460, Seq. Id. No. 461, Seq. Id. No. 462, Seq. Id. No. 463, Seq. Id. No. 464, Seq. Id. No. 465, Seq. Id. No. 466, Seq. Id. No. 467, Seq. Id. No. 468, Seq. Id. No. 469, Seq. Id. No. 470, Seq. Id. No. 471, Seq. Id. No. 472, Seq. Id. No. 473, Seq. Id. No. 474, Seq. Id. No. 475, Seq. Id. No. 476, Seq. Id. No. 477, Seq. Id. No. 478, Seq. Id. No. 479, Seq. Id. No. 480, Seq. Id. No. 481, Seq. Id. No. 482, Seq. Id. No. 483, Seq. Id. No. 484, Seq. Id. No. 485, Seq. Id. No. 486, Seq. Id. No. 487, Seq. Id. No. 488, Seq. Id. No. 489, Seq. Id. No. 490, Seq. Id. No. 491, Seq. Id. No. 492, Seq. Id. No. 493, Seq. Id. No. 494, Seq. Id. No. 495, Seq. Id. No. 496, Seq. Id. No. 497, Seq. Id. No. 498, Seq. Id. No. 499, Seq. Id. No. 500, Seq. Id. No. 501, Seq. Id. No. 502, Seq. Id. No. 503, Seq. Id. No. 504, Seq. Id. No. 505, Seq. Id. No. 506, Seq. Id. No. 507, Seq. Id. No. 508, Seq. Id. No. 509, Seq. Id. No. 510, Seq. Id. No. 511, Seq. Id. No. 512, Seq. Id. No. 513, Seq. Id. No. 514, Seq. Id. No. 515, Seq. Id. No. 516, Seq. Id. No. 517, Seq. Id. No. 518, Seq. Id. No. 519, Seq. Id. No. 520, Seq. Id. No. 521, Seq. Id. No. 522, Seq. Id. No. 523, Seq. Id. No. 524, Seq. Id. No. 525, Seq. Id. No. 526, Seq. Id. No. 527, Seq. Id. No. 528, Seq. Id. No. 529, Seq. Id. No. 530, Seq. Id. No. 531, Seq. Id. No. 532, Seq. Id. No. 533, Seq. Id. No. 534, Seq. Id. No. 535, Seq. Id. No. 536, Seq. Id. No. 537, Seq. Id. No. 538, Seq. Id. No. 539, Seq. Id. No. 540, Seq. Id. No. 541, Seq. Id. No. 542, Seq. Id. No. 543, Seq. Id. No. 544, Seq. Id. No. 545, Seq. Id. No. 546, Seq. Id. No. 547, Seq. Id. No. 548, Seq. Id. No. 549, Seq. Id. No. 550, Seq. Id. No. 551, Seq. Id. No. 552, Seq. Id. No. 553, Seq. Id. No. 554, Seq. Id. No. 555, Seq. Id. No. 556, Seq. Id. No. 557, Seq. Id. No. 558, Seq. Id. No. 559, Seq. Id. No. 560, Seq. Id. No. 561, Seq. Id. No. 562, Seq. Id. No. 563, Seq. Id. No. 564, Seq. Id. No. 565, Seq. Id. No. 566, Seq. Id. No. 567, Seq. Id. No. 568, Seq. Id. No. 569, Seq. Id. No. 570, Seq. Id. No. 571, Seq. Id. No. 572, Seq. Id. No. 573, Seq. Id. No. 574, Seq. Id. No. 575, Seq. Id. No. 576, Seq. Id. No. 577, Seq. Id. No. 578, Seq. Id. No. 579, Seq. Id. No. 580, Seq. Id. No. 581, Seq. Id. No. 582, Seq. Id. No. 583, Seq. Id. No. 584, Seq. Id. No. 585, Seq. Id. No. 586, Seq. Id. No. 587, Seq. Id. No. 588, Seq. Id. No. 589, Seq. Id. No. 590, Seq. Id. No. 591, Seq. Id. No. 592, Seq. Id. No. 593, Seq. Id. No. 594, Seq. Id. No. 595, Seq. Id. No. 596, Seq. Id. No. 597, Seq. Id. No. 598, Seq. Id. No. 599, Seq. Id. No. 600, Seq. Id. No. 601, Seq. Id. No. 602, Seq. Id. No. 603, Seq. Id. No. 604, Seq. Id. No. 605, Seq. Id. No. 606, Seq. Id. No. 607, Seq. Id. No. 608, Seq. Id. No. 609, Seq. Id. No. 610, Seq. Id. No. 611, Seq. Id. No. 612, Seq. Id. No. 613, Seq. Id. No. 614, Seq. Id. No. 615, Seq. Id. No. 616, Seq. Id. No. 617, Seq. Id. No. 618, and Seq. Id. No. 619.
  • A certain embodiment of present invention provides a method as described above, wherein the autoantibody recognizes an EGFR peptide that is selected from the group consisting of Seq. Id. No. 3, Seq. Id. No. 8, Seq. Id. No. 9, Seq. Id. No. 10, Seq. Id. No. 11, Seq. Id. No. 12, Seq. Id. No. 13, Seq. Id. No. 14, Seq. Id. No. 64, Seq. Id. No. 102, Seq. Id. No. 309, Seq. Id. No. 370, Seq. Id. No. 373, Seq. Id. No. 519, Seq. Id. No. 520, Seq. Id. No. 521, Seq. Id. No. 525, Seq. Id. No. 556, Seq. Id. No. 558, Seq. Id. No. 561, Seq. Id. No. 566, Seq. Id. No. 600, Seq. Id. No. 602 and Seq. Id. No. 603.
  • A certain embodiment of present invention provides a kit for detecting in a blood sample of the human subject a level of one or more autoantibodies selected from the group of autoantibodies recognizing human EGFR, wherein an increased level of said autoantibodies selected from the group of autoantibodies recognizing human EGFR in the blood sample of the human subject compared to a level of said autoantibodies representative for a human subject of a healthy population is indicative for non-small cell lung cancer.
  • A certain embodiment of present invention provides a kit as described above, wherein the autoantibody recognizes an EGFR peptide that is selected from the group consisting of Seq. Id. No. 3, Seq. Id. No. 8, Seq. Id. No. 9, Seq. Id. No. 10, Seq. Id. No. 11, Seq. Id. No. 12, Seq. Id. No. 13, Seq. Id. No. 14, Seq. Id. No. 64, Seq. Id. No. 102, Seq. Id. No. 309, Seq. Id. No. 370, Seq. Id. No. 373, Seq. Id. No. 519, Seq. Id. No. 520, Seq. Id. No. 521, Seq. Id. No. 525, Seq. Id. No. 556, Seq. Id. No. 558, Seq. Id. No. 561, Seq. Id. No. 566, Seq. Id. No. 600, Seq. Id. No. 602 and Seq. Id. No. 603.
  • A certain embodiment of present invention provides a kit according as described herein, wherein the autoantibody recognizes a mutated EGFR peptide that is selected from Seq. Id. No. 554, Seq. Id. No. 555, Seq. Id. No. 556, Seq. Id. No. 557, Seq. Id. No. 558, Seq. Id. No. 559, and Seq. Id. No. 560.
  • A certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 518.
  • A certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 519.
  • A certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 520.
  • A certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 521.
  • A certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 522.
  • A certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 523.
  • A certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 524.
  • A certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 525.
  • A certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 526.
  • A certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 527.
  • A certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 528.
  • A certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 529.
  • A certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 530.
  • A certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 531.
  • A certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 532.
  • A certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 533.
  • A certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 534.
  • A certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 535.
  • A certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 536.
  • A certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 537.
  • A certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 538.
  • A certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 539.
  • A certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 540.
  • A certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 541.
  • A certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 542.
  • A certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 543.
  • A certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 544.
  • A certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 545.
  • A certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 546.
  • A certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 547.
  • A certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 548.
  • A certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 549.
  • A certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 550.
  • A certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 551.
  • A certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 552.
  • A certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 553.
  • A certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 554.
  • A certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 555.
  • A certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 556.
  • A certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 557.
  • A certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 558.
  • A certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 559.
  • A certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 560.
  • A certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 561.
  • A certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 562.
  • A certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 563.
  • A certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 564.
  • A certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 565.
  • A certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 566.
  • A certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 567.
  • A certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 568.
  • A certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 569.
  • A certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 570.
  • A certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 571.
  • A certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 572.
  • A certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 573.
  • A certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 574.
  • A certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 575.
  • A certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 576.
  • A certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 577.
  • A certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 578.
  • A certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 579.
  • A certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 580.
  • A certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 581.
  • A certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 582.
  • A certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 583.
  • A certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 584.
  • A certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 585.
  • A certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 586.
  • A certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 587.
  • A certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 588.
  • A certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 589.
  • A certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 590.
  • A certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 591.
  • A certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 592.
  • A certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 593.
  • A certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 594.
  • A certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 595.
  • A certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 596.
  • A certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 597.
  • A certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 598.
  • A certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 599.
  • A certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 600.
  • A certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 601.
  • A certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 602.
  • A certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 603.
  • A certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 604.
  • A certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 605.
  • A certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 606.
  • A certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 607.
  • A certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 608.
  • A certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 609.
  • A certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 610.
  • A certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 611.
  • A certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 612.
  • A certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 613.
  • A certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 614.
  • A certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 615.
  • A certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 616.
  • A certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 617.
  • A certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 618.
  • A certain embodiment of present invention provides a method as described herein, wherein the autoantibody recognizes an EGFR peptide of Seq. Id. No. 619.
  • A certain embodiment of present invention provides a method as described herein, wherein the level of an autoantibody recognizing p53 is measured.
  • A certain embodiment of present invention provides a method as described herein, wherein the level of an autoantibody in the blood sample of the human subject is 5 times higher than the level of said autoantibody representative for a human subject of a healthy population.
  • A certain embodiment of present invention provides a method for determining the EGFR mutation status in a tumor tissue of a human subject suffering from non-small cell lung cancer comprising:
  • detecting in a blood sample of a human being suffering from non-small cell lung cancer an autoantibody selected from the group of autoantibodies recognizing an human EGFR peptide as described herein, wherein the presence of said autoantibody is indicative for the presence of a mutation of exon 19 in the gene encoding EGFR in human tissue.
  • A certain embodiment of present invention provides a method for determining the EGFR mutation status in a tumor tissue of a human subject suffering from non-small cell lung cancer comprising:
  • detecting in a blood sample of a human being suffering from non-small cell lung cancer an autoantibody selected from the group of autoantibodies recognizing an human EGFR peptide as described herein, wherein the presence of said autoantibody is indicative for the presence of a deletion of exon 21 in the gene encoding EGFR in human tissue.
  • A certain embodiment of present invention provides erlotinib or a pharmaceutically acceptable salt thereof, in particular erlotinib hydrochloride, for use in treating a NSCLC patient identified by a method as described herein comprising administering erlotinib or a pharmaceutically acceptable salt thereof, in particular erlotinib hydrochloride to the patient.
  • A certain embodiment of present invention provides the use of an autoantibody for predicting the response of a NSCLC patient to erlotinib or a pharmaceutically acceptable salt thereof, in particular erlotinib hydrochloride, treatment, which antibody was identified by a method as described herein.
  • A certain embodiment of present invention provides a kit for detecting in a blood sample of the human subject a level of one or more autoantibodies selected from the group of autoantibodies recognizing human EGFR, wherein an increased level of said autoantibodies selected from the group of autoantibodies recognizing human EGFR in the blood sample of the human subject compared to a level of said autoantibodies representative for a human subject of a healthy population is indicative for non-small cell lung cancer.
  • A certain embodiment of present invention provides a kit according as described herein, wherein the autoantibody recognizes an EGFR peptide that is selected from Seq. Id. No. 1-Seq. Id. No. 15.
  • A certain embodiment of present invention provides a kit according as described herein, wherein the autoantibody recognizes an EGFR peptide that is selected from Seq. Id. No. 16-Seq. Id. No. 517.
  • A certain embodiment of present invention provides a kit according as described herein, wherein the autoantibody recognizes an EGFR peptide that is selected from Seq. Id. No. 518-Seq. Id. No. 602.
  • A certain embodiment of present invention provides a kit according as described herein, wherein the autoantibody recognizes an EGFR peptide that is selected from Seq. Id. No. 603-Seq. Id. No. 619.
  • A certain embodiment of present invention provides a kit according as described herein, wherein the autoantibody recognizes an EGFR peptide that is selected from Seq. Id. No. 519, Seq. Id. No. 520, Seq. Id. No. 521, and Seq. Id. No. 561.
    • FIGURES AND SEQ. ID. NUMBERS
  • FIG. 1: Log-transformed values of peptide binding for all peptides grouped by patient (49 samples, 4-digit numbers) and controls (1-digit numbers). Patients have on average higher signals, with a number of antibodies binding to peptides stronger than any signal in control sera.
  • FIG. 2: Histogram of distribution of the p-values for the significance of the antibody titers in a Cox regression model of OS or PFS˜EGFR+TRT+EGFR:TRT+SEX+Antibody titer+ Antibody titer:TRT. If antibody titers do not affect survival, a uniform distribution is expected. The deviation from the uniform distribution is highly significant, which lead to the conclusion that approximately 50% of the 245 antibody titers with p-values<0.05 will have a significant influence on progression free survival. A similar model calculation for overall survival (OS) yields 663 candidates at p-Values<0.05 with a slightly better false discovery rate of approximately 40%.
  • FIG. 3: Venn diagrams illustrating the refinement of peptide candidates for (A) progression free survival and (B) overall survival. Pep—initial peptide selection form Cox-regression model with all covariates; RASH: overlapping sequences from peptides predicting PFS (OS) in patients with rash in a proportional hazard model; TRT: overlapping sequences from peptides predicting PFS (OS) in the erlotinib subgroup; EC4: univariate test of response (after 4 cycles, categorical) vs. antibody titer.
  • FIG. 4: Presence of autoantibodies against a mutated EGFR peptide predicts (p=0.006) a better treatment outcome in the Tarceva® arm of the trial independent of the occurrence of rash.
    •
  • TABLE 4 
    Seq. Id. No. 1-619 of human EGFR 
    peptides, *indicates mutated EGFR
    Seq.
    Id. No. protein sequence
      1* GEKVKIPVAIKPKANK
      2* GEKVKIPVAIKSPKANK
     3 KEYHAEGGKVPIKWM
      4* KIPVAIKHPTSPK
      5* KIPVAIKKPTSPK
      6* KIPVAIKPTSPK
      7* KIPVAIKRPTSPK
     8 MPFGCLLDYVREH
     9 NSTFDSPAHWAQKGSHQI
    10 PREFVENSECIQCHPECL
    11 RGPDNCIQCAHYIDGPHCVKTCP
    12 RMHLPSPTDSNFYRA
    13 SIDDTFLPVPEYIN
    14 VRKCKKCEGPCRKV
     15* VRKSKKSEGPSRKV
     16* ADKDILDEAYVMACA
     17* ADKDILDEAYVMACG
     18* ADKDILDEAYVMACV
     19* ADKDILDEAYVMAIA
     20* ADKDILDEAYVMAIG
     21* ADKDILDEAYVMAIV
     22* ADKDILDEAYVMANA
     23* ADKDILDEAYVMANG
     24* ADKDILDEAYVMANV
     25* ADKDILDEAYVMASA
     26* ADKDILDEAYVMASG
     27* ADKDILDEAYVMASV
     28* ADKDILDEAYVMTCA
     29* ADKDILDEAYVMTCG
     30* ADKDILDEAYVMTCV
     31* ADKDILDEAYVMTIA
     32* ADKDILDEAYVMTIG
     33* ADKDILDEAYVMTIV
     34* ADKDILDEAYVMTNA
     35* ADKDILDEAYVMTNG
     36* ADKDILDEAYVMTNV
     37* ADKDILDEAYVMTSA
     38* ADKDILDEAYVMTSG
     39* ADKDILDEAYVMTSV
     40* ADKEILDEAYVMACA
     41* ADKEILDEAYVMACG
     42* ADKEILDEAYVMACV
     43* ADKEILDEAYVMAIA
     44* ADKEILDEAYVMAIG
     45* ADKEILDEAYVMAIV
     46* ADKEILDEAYVMANA
     47* ADKEILDEAYVMANG
     48* ADKEILDEAYVMANV
     49* ADKEILDEAYVMASA
     50* ADKEILDEAYVMASG
     51* ADKEILDEAYVMASV
     52* ADKEILDEAYVMTCA
     53* ADKEILDEAYVMTCG
     54* ADKEILDEAYVMTCV
     55* ADKEILDEAYVMTIA
     56* ADKEILDEAYVMTIG
     57* ADKEILDEAYVMTIV
     58* ADKEILDEAYVMTNA
     59* ADKEILDEAYVMTNG
     60* ADKEILDEAYVMTNV
     61* ADKEILDEAYVMTSA
     62* ADKEILDEAYVMTSG
     63* ADKEILDEAYVMTSV
    64 AIKELREATSPKA
     65* AIKILREATSPKA
     66* AIKVLREATSPKA
     67* ANKDILDEAYVMACA
     68* ANKDILDEAYVMACG
     69* ANKDILDEAYVMACV
     70* ANKDILDEAYVMAIA
     71* ANKDILDEAYVMAIG
     72* ANKDILDEAYVMAIV
     73* ANKDILDEAYVMANA
     74* ANKDILDEAYVMANG
     75* ANKDILDEAYVMANV
     76* ANKDILDEAYVMASA
     77* ANKDILDEAYVMASG
     78* ANKDILDEAYVMASV
     79* ANKDILDEAYVMTCA
     80* ANKDILDEAYVMTCG
     81* ANKDILDEAYVMTCV
     82* ANKDILDEAYVMTIA
     83* ANKDILDEAYVMTIG
     84* ANKDILDEAYVMTIV
     85* ANKDILDEAYVMTNA
     86* ANKDILDEAYVMTNG
     87* ANKDILDEAYVMTNV
     88* ANKDILDEAYVMTSA
     89* ANKDILDEAYVMTSG
     90* ANKDILDEAYVMTSV
     91* ANKEILDEAYVMACA
     92* ANKEILDEAYVMACG
     93* ANKEILDEAYVMACV
     94* ANKEILDEAYVMAIA
     95* ANKEILDEAYVMAIG
     96* ANKEILDEAYVMAIV
     97* ANKEILDEAYVMANA
     98* ANKEILDEAYVMANG
     99* ANKEILDEAYVMANV
    100* ANKEILDEAYVMASA
    101* ANKEILDEAYVMASG
    102  ANKEILDEAYVMASV
    103* ANKEILDEAYVMTCA
    104* ANKEILDEAYVMTCG
    105* ANKEILDEAYVMTCV
    106* ANKEILDEAYVMTIA
    107* ANKEILDEAYVMTIG
    108* ANKEILDEAYVMTIV
    109* ANKEILDEAYVMTNA
    110* ANKEILDEAYVMTNG
    111* ANKEILDEAYVMTNV
    112* ANKEILDEAYVMTSA
    113* ANKEILDEAYVMTSG
    114* ANKEILDEAYVMTSV
    115* ASKDILDEAYVMACA
    116* ASKDILDEAYVMACG
    117* ASKDILDEAYVMACV
    118* ASKDILDEAYVMAIA
    119* ASKDILDEAYVMAIG
    120* ASKDILDEAYVMAIV
    121* ASKDILDEAYVMANA
    122* ASKDILDEAYVMANG
    123* ASKDILDEAYVMANV
    124* ASKDILDEAYVMASA
    125* ASKDILDEAYVMASG
    126* ASKDILDEAYVMASV
    127* ASKDILDEAYVMTCA
    128* ASKDILDEAYVMTCG
    129* ASKDILDEAYVMTCV
    130* ASKDILDEAYVMTIA
    131* ASKDILDEAYVMTIG
    132* ASKDILDEAYVMTIV
    133* ASKDILDEAYVMTNA
    134* ASKDILDEAYVMTNG
    135* ASKDILDEAYVMTNV
    136* ASKDILDEAYVMTSA
    137* ASKDILDEAYVMTSG
    138* ASKDILDEAYVMTSV
    139* ASKEILDEAYVMACA
    140* ASKEILDEAYVMACG
    141* ASKEILDEAYVMACV
    142* ASKEILDEAYVMAIA
    143* ASKEILDEAYVMAIG
    144* ASKEILDEAYVMAIV
    145* ASKEILDEAYVMANA
    146* ASKEILDEAYVMANG
    147* ASKEILDEAYVMANV
    148* ASKEILDEAYVMASA
    149* ASKEILDEAYVMASG
    150* ASKEILDEAYVMASV
    151* ASKEILDEAYVMTCA
    152* ASKEILDEAYVMTCG
    153* ASKEILDEAYVMTCV
    154* ASKEILDEAYVMTIA
    155* ASKEILDEAYVMTIG
    156* ASKEILDEAYVMTIV
    157* ASKEILDEAYVMTNA
    158* ASKEILDEAYVMTNG
    159* ASKEILDEAYVMTNV
    160* ASKEILDEAYVMTSA
    161* ASKEILDEAYVMTSG
    162* ASKEILDEAYVMTSV
    163* CLLVHRDLAARNV
    164* CRLVHRDLAARNV
    165* DDKDILDEAYVMACA
    166* DDKDILDEAYVMACG
    167* DDKDILDEAYVMACV
    168* DDKDILDEAYVMAIA
    169* DDKDILDEAYVMAIG
    170* DDKDILDEAYVMAIV
    171* DDKDILDEAYVMANA
    172* DDKDILDEAYVMANG
    173* DDKDILDEAYVMANV
    174* DDKDILDEAYVMASA
    175* DDKDILDEAYVMASG
    176* DDKDILDEAYVMASV
    177* DDKDILDEAYVMTCA
    178* DDKDILDEAYVMTCG
    179* DDKDILDEAYVMTCV
    180* DDKDILDEAYVMTIA
    181* DDKDILDEAYVMTIG
    182* DDKDILDEAYVMTIV
    183* DDKDILDEAYVMTNA
    184* DDKDILDEAYVMTNG
    185* DDKDILDEAYVMTNV
    186* DDKDILDEAYVMTSA
    187* DDKDILDEAYVMTSG
    188* DDKDILDEAYVMTSV
    189* DDKEILDEAYVMACA
    190* DDKEILDEAYVMACG
    191* DDKEILDEAYVMACV
    192* DDKEILDEAYVMAIA
    193* DDKEILDEAYVMAIG
    194* DDKEILDEAYVMAIV
    195* DDKEILDEAYVMANA
    196* DDKEILDEAYVMANG
    197* DDKEILDEAYVMANV
    198* DDKEILDEAYVMASA
    199* DDKEILDEAYVMASG
    200* DDKEILDEAYVMASV
    201* DDKEILDEAYVMTCA
    202* DDKEILDEAYVMTCG
    203* DDKEILDEAYVMTCV
    204* DDKEILDEAYVMTIA
    205* DDKEILDEAYVMTIG
    206* DDKEILDEAYVMTIV
    207* DDKEILDEAYVMTNA
    208* DDKEILDEAYVMTNG
    209* DDKEILDEAYVMTNV
    210* DDKEILDEAYVMTSA
    211* DDKEILDEAYVMTSG
    212* DDKEILDEAYVMTSV
    213* DNKDILDEAYVMACA
    214* DNKDILDEAYVMACG
    215* DNKDILDEAYVMACV
    216* DNKDILDEAYVMAIA
    217* DNKDILDEAYVMAIG
    218* DNKDILDEAYVMAIV
    219* DNKDILDEAYVMANA
    220* DNKDILDEAYVMANG
    221* DNKDILDEAYVMANV
    222* DNKDILDEAYVMASA
    223* DNKDILDEAYVMASG
    224* DNKDILDEAYVMASV
    225* DNKDILDEAYVMTCA
    226* DNKDILDEAYVMTCG
    227* DNKDILDEAYVMTCV
    228* DNKDILDEAYVMTIA
    229* DNKDILDEAYVMTIG
    230* DNKDILDEAYVMTIV
    231* DNKDILDEAYVMTNA
    232* DNKDILDEAYVMTNG
    233* DNKDILDEAYVMTNV
    234* DNKDILDEAYVMTSA
    235* DNKDILDEAYVMTSG
    236* DNKDILDEAYVMTSV
    237* DNKEILDEAYVMACA
    238* DNKEILDEAYVMACG
    239* DNKEILDEAYVMACV
    240* DNKEILDEAYVMAIA
    241* DNKEILDEAYVMAIG
    242* DNKEILDEAYVMAIV
    243* DNKEILDEAYVMANA
    244* DNKEILDEAYVMANG
    245* DNKEILDEAYVMANV
    246* DNKEILDEAYVMASA
    247* DNKEILDEAYVMASG
    248* DNKEILDEAYVMASV
    249* DNKEILDEAYVMTCA
    250* DNKEILDEAYVMTCG
    251* DNKEILDEAYVMTCV
    252* DNKEILDEAYVMTIA
    253* DNKEILDEAYVMTIG
    254* DNKEILDEAYVMTIV
    255* DNKEILDEAYVMTNA
    256* DNKEILDEAYVMTNG
    257* DNKEILDEAYVMTNV
    258* DNKEILDEAYVMTSA
    259* DNKEILDEAYVMTSG
    260* DNKEILDEAYVMTSV
    261* DSKDILDEAYVMACA
    262* DSKDILDEAYVMACG
    263* DSKDILDEAYVMACV
    264* DSKDILDEAYVMAIA
    265* DSKDILDEAYVMAIG
    266* DSKDILDEAYVMAIV
    267* DSKDILDEAYVMANA
    268* DSKDILDEAYVMANG
    269* DSKDILDEAYVMANV
    270* DSKDILDEAYVMASA
    271* DSKDILDEAYVMASG
    272* DSKDILDEAYVMASV
    273* DSKDILDEAYVMTCA
    274* DSKDILDEAYVMTCG
    275* DSKDILDEAYVMTCV
    276* DSKDILDEAYVMTIA
    277* DSKDILDEAYVMTIG
    278* DSKDILDEAYVMTIV
    279* DSKDILDEAYVMTNA
    280* DSKDILDEAYVMTNG
    281* DSKDILDEAYVMTNV
    282* DSKDILDEAYVMTSA
    283* DSKDILDEAYVMTSG
    284* DSKDILDEAYVMTSV
    285* DSKEILDEAYVMACA
    286* DSKEILDEAYVMACG
    287* DSKEILDEAYVMACV
    288* DSKEILDEAYVMAIA
    289* DSKEILDEAYVMAIG
    290* DSKEILDEAYVMAIV
    291* DSKEILDEAYVMANA
    292* DSKEILDEAYVMANG
    293* DSKEILDEAYVMANV
    294* DSKEILDEAYVMASA
    295* DSKEILDEAYVMASG
    296* DSKEILDEAYVMASV
    297* DSKEILDEAYVMTCA
    298* DSKEILDEAYVMTCG
    299* DSKEILDEAYVMTCV
    300* DSKEILDEAYVMTIA
    301* DSKEILDEAYVMTIG
    302* DSKEILDEAYVMTIV
    303* DSKEILDEAYVMTNA
    304* DSKEILDEAYVMTNG
    305* DSKEILDEAYVMTNV
    306* DSKEILDEAYVMTSA
    307* DSKEILDEAYVMTSG
    308* DSKEILDEAYVMTSV
    309  HYQDPHSTAVGNPEY
    310* KVKIPVAIAPSPKA
    311* KVKIPVAIATSPKA
    312* KVKIPVAIEAPSPKA
    313* KVKIPVAIEATSPKA
    314* KVKIPVAIEEAPSPKA
    315* KVKIPVAIEEATSPKA
    316* KVKIPVAIEEPSPKA
    317* KVKIPVAIEETSPKA
    318* KVKIPVAIEPSPKA
    319* KVKIPVAIERAPSPKA
    320* KVKIPVAIERATSPKA
    321* KVKIPVAIEREAPSPKA
    322* KVKIPVAIEREATSPKA
    323* KVKIPVAIEREPSPKA
    324* KVKIPVAIERETSPKA
    325* KVKIPVAIERPSPKA
    326* KVKIPVAIERTSPKA
    327* KVKIPVAIETSPKA
    328* KVKIPVAIKAPSPKA
    329* KVKIPVAIKATSPKA
    330* KVKIPVAIKEAPSPKA
    331* KVKIPVAIKEATSPKA
    332* KVKIPVAIKEEAPSPKA
    333* KVKIPVAIKEEATSPKA
    334* KVKIPVAIKEEPSPKA
    335* KVKIPVAIKEETSPKA
    336* KVKIPVAIKEPSPKA
    337* KVKIPVAIKERAPSPKA
    338* KVKIPVAIKERATSPKA
    339* KVKIPVAIKEREAPSPKA
    340* KVKIPVAIKEREATSPKA
    341* KVKIPVAIKEREPSPKA
    342* KVKIPVAIKERETSPKA
    343* KVKIPVAIKERPSPKA
    344* KVKIPVAIKERTSPKA
    345* KVKIPVAIKETSPKA
    346* KVKIPVAIKPSPKA
    347* KVKIPVAIKRAPSPKA
    348* KVKIPVAIKRATSPKA
    349* KVKIPVAIKREAPSPKA
    350* KVKIPVAIKREATSPKA
    351* KVKIPVAIKREPSPKA
    352* KVKIPVAIKRETSPKA
    353* KVKIPVAIKRPSPKA
    354* KVKIPVAIKRTSPKA
    355* KVKIPVAIKTSPKA
    356* KVKIPVAIPSPKA
    357* KVKIPVAIRAPSPKA
    358* KVKIPVAIRATSPKA
    359* KVKIPVAIREAPSPKA
    360* KVKIPVAIREATSPKA
    361* KVKIPVAIREP SPKA
    362* KVKIPVAIRETSPKA
    363* KVKIPVAIRPSPKA
    364* KVKIPVAIRTSPKA
    365* KVKIPVAITSPKA
    366* LREEILDEAYVMA
    367* LREPILDEAYVMA
    368* PEGEKAKIPVAIKELREA
    369* PEGEKAKIPVAIRELREA
    370  PEGEKVKIPVAIKELREA
    371* PEGEKVKIPVAIRELREA
    372* RLLVHRDLAARNV
    373  RRLVHRDLAARNV
    374* SDKDILDEAYVMACA
    375* SDKDILDEAYVMACG
    376* SDKDILDEAYVMACV
    377* SDKDILDEAYVMAIA
    378* SDKDILDEAYVMAIG
    379* SDKDILDEAYVMAIV
    380* SDKDILDEAYVMANA
    381* SDKDILDEAYVMANG
    382* SDKDILDEAYVMANV
    383* SDKDILDEAYVMASA
    384* SDKDILDEAYVMASG
    385* SDKDILDEAYVMASV
    386* SDKDILDEAYVMTCA
    387* SDKDILDEAYVMTCG
    388* SDKDILDEAYVMTCV
    389* SDKDILDEAYVMTIA
    390* SDKDILDEAYVMTIG
    391* SDKDILDEAYVMTIV
    392* SDKDILDEAYVMTNA
    393* SDKDILDEAYVMTNG
    394* SDKDILDEAYVMTNV
    395* SDKDILDEAYVMTSA
    396* SDKDILDEAYVMTSG
    397* SDKDILDEAYVMTSV
    398* SDKEILDEAYVMACA
    399* SDKEILDEAYVMACG
    400* SDKEILDEAYVMACV
    401* SDKEILDEAYVMAIA
    402* SDKEILDEAYVMAIG
    403* SDKEILDEAYVMAIV
    404* SDKEILDEAYVMANA
    405* SDKEILDEAYVMANG
    406* SDKEILDEAYVMANV
    407* SDKEILDEAYVMASA
    408* SDKEILDEAYVMASG
    409* SDKEILDEAYVMASV
    410* SDKEILDEAYVMTCA
    411* SDKEILDEAYVMTCG
    412* SDKEILDEAYVMTCV
    413* SDKEILDEAYVMTIA
    414* SDKEILDEAYVMTIG
    415* SDKEILDEAYVMTIV
    416* SDKEILDEAYVMTNA
    417* SDKEILDEAYVMTNG
    418* SDKEILDEAYVMTNV
    419* SDKEILDEAYVMTSA
    420* SDKEILDEAYVMTSG
    421* SDKEILDEAYVMTSV
    422* SNKDILDEAYVMACA
    423* SNKDILDEAYVMACG
    424* SNKDILDEAYVMACV
    425* SNKDILDEAYVMAIA
    426* SNKDILDEAYVMAIG
    427* SNKDILDEAYVMAIV
    428* SNKDILDEAYVMANA
    429* SNKDILDEAYVMANG
    430* SNKDILDEAYVMANV
    431* SNKDILDEAYVMASA
    432* SNKDILDEAYVMASG
    433* SNKDILDEAYVMASV
    434* SNKDILDEAYVMTCA
    435* SNKDILDEAYVMTCG
    436* SNKDILDEAYVMTCV
    437* SNKDILDEAYVMTIA
    438* SNKDILDEAYVMTIG
    439* SNKDILDEAYVMTIV
    440* SNKDILDEAYVMTNA
    441* SNKDILDEAYVMTNG
    442* SNKDILDEAYVMTNV
    443* SNKDILDEAYVMTSA
    444* SNKDILDEAYVMTSG
    445* SNKDILDEAYVMTSV
    446* SNKEILDEAYVMACA
    447* SNKEILDEAYVMACG
    448* SNKEILDEAYVMACV
    449* SNKEILDEAYVMAIA
    450* SNKEILDEAYVMAIG
    451* SNKEILDEAYVMAIV
    452* SNKEILDEAYVMANA
    453* SNKEILDEAYVMANG
    454* SNKEILDEAYVMANV
    455* SNKEILDEAYVMASA
    456* SNKEILDEAYVMASG
    457* SNKEILDEAYVMASV
    458* SNKEILDEAYVMTCA
    459* SNKEILDEAYVMTCG
    460* SNKEILDEAYVMTCV
    461* SNKEILDEAYVMTIA
    462* SNKEILDEAYVMTIG
    463* SNKEILDEAYVMTIV
    464* SNKEILDEAYVMTNA
    465* SNKEILDEAYVMTNG
    466* SNKEILDEAYVMTNV
    467* SNKEILDEAYVMTSA
    468* SNKEILDEAYVMTSG
    469* SNKEILDEAYVMTSV
    470* SSKDILDEAYVMACA
    471* SSKDILDEAYVMACG
    472* SSKDILDEAYVMACV
    473* SSKDILDEAYVMAIA
    474* SSKDILDEAYVMAIG
    475* SSKDILDEAYVMAIV
    476* SSKDILDEAYVMANA
    477* SSKDILDEAYVMANG
    478* SSKDILDEAYVMANV
    479* SSKDILDEAYVMASA
    480* SSKDILDEAYVMASG
    481* SSKDILDEAYVMASV
    482* SSKDILDEAYVMTCA
    483* SSKDILDEAYVMTCG
    484* SSKDILDEAYVMTCV
    485* SSKDILDEAYVMTIA
    486* SSKDILDEAYVMTIG
    487* SSKDILDEAYVMTIV
    488* SSKDILDEAYVMTNA
    489* SSKDILDEAYVMTNG
    490* SSKDILDEAYVMTNV
    491* SSKDILDEAYVMTSA
    492* SSKDILDEAYVMTSG
    493* SSKDILDEAYVMTSV
    494* SSKEILDEAYVMACA
    495* SSKEILDEAYVMACG
    496* SSKEILDEAYVMACV
    497* SSKEILDEAYVMAIA
    498* SSKEILDEAYVMAIG
    499* SSKEILDEAYVMAIV
    500* SSKEILDEAYVMANA
    501* SSKEILDEAYVMANG
    502* SSKEILDEAYVMANV
    503* SSKEILDEAYVMASA
    504* SSKEILDEAYVMASG
    505* SSKEILDEAYVMASV
    506* SKEILDEAYVMTCA
    507* SSKEILDEAYVMTCG
    508* SSKEILDEAYVMTCV
    509* SSKEILDEAYVMTIA
    510* SSKEILDEAYVMTIG
    511* SSKEILDEAYVMTIV
    512* SSKEILDEAYVMTNA
    513* SSKEILDEAYVMTNG
    514* SSKEILDEAYVMTNV
    515* SSKEILDEAYVMTSA
    516* SSKEILDEAYVMTSG
    517* SSKEILDEAYVMTSV
    518* AVVMASVDNPHVCR
    519  AYVMASVDNPHVCR
    520  CTGPGLEGCPTNG
    521  DEAYVMASVDNPHVCRLLG
    522* ILKETEFKKIFVLGPGAFGT
    523* ILKETEFKKIFVLGSGAFGT
    524* ILKETEFKKIKVLGPGAFGT
    525  ILKETEFKKIKVLGSGAFGT
    526* ILKETEFKKLFVLGPGAFGT
    527* ILKETEFKKLFVLGSGAFGT
    528* ILKETEFKKLKVLGPGAFGT
    529* ILKETEFKKLKVLGSGAFGT
    530* ILKETELKKIFVLGPGAFGT
    531* ILKETELKKIFVLGSGAFGT
    532* ILKETELKKIKVLGPGAFGT
    533* ILKETELKKIKVLGSGAFGT
    534* ILKETELKKLFVLGPGAFGT
    535* ILKETELKKLFVLGSGAFGT
    536* ILKETELKKLKVLGPGAFGT
    537* ILKETELKKLKVLGSGAFGT
    538* ILMETEFKKIFVLGPGAFGT
    539* ILMETEFKKIFVLGSGAFGT
    540* ILMETEFKKIKVLGPGAFGT
    541* ILMETEFKKIKVLGSGAFGT
    542* ILMETEFKKLFVLGPGAFGT
    543* ILMETEFKKLFVLGSGAFGT
    544* ILMETEFKKLKVLGPGAFGT
    545* ILMETEFKKLKVLGSGAFGT
    546* ILMETELKKIFVLGPGAFGT
    547* ILMETELKKIFVLGSGAFGT
    548* ILMETELKKIKVLGPGAFGT
    549* ILMETELKKIKVLGSGAFGT
    550* ILMETELKKLFVLGPGAFGT
    551* ILMETELKKLFVLGSGAFGT
    552* ILMETELKKLKVLGPGAFGT
    553* ILMETELKKLKVLGSGAFGT
    554* KGNYVVTDHGSCVRA
    555* KVKIPVAIKAPKA
    556  KVKIPVAIKELREATSPKA
    557* KVKIPVAIKSPKA
    558  LLRILKETEFKKI
    559* LLRILKETESKKI
    560* MNYLEDRLLVHRD
    561  MNYLEDRRLVHRD
    562* RLLQERELLEPLTPSGEAPNQAFLR
    563* RLLQERELLEPLTPSGEAPNQALLR
    564* RLLQERELLEPLTPSGEAPNQAPLR
    565* RLLQERELVEPLTPSGEAPNQAFLR
    566  RLLQERELVEPLTPSGEAPNQALLR
    567* RLLQERELVEPLTPSGEAPNQAPLR
    568* TLKETEFKKIFVLGPGAFGT
    569* TLKETEFKKIFVLGSGAFGT
    570* TLKETEFKKIKVLGPGAFGT
    571* TLKETEFKKIKVLGSGAFGT
    572* TLKETEFKKLFVLGPGAFGT
    573* TLKETEFKKLFVLGSGAFGT
    574* TLKETEFKKLKVLGPGAFGT
    575* TLKETEFKKLKVLGSGAFGT
    576* TLKETELKKIFVLGPGAFGT
    577* TLKETELKKIFVLGSGAFGT
    578* TLKETELKKIKVLGPGAFGT
    579* TLKETELKKIKVLGSGAFGT
    580* TLKETELKKLFVLGPGAFGT
    581* TLKETELKKLFVLGSGAFGT
    582* TLKETELKKLKVLGPGAFGT
    583* TLKETELKKLKVLGSGAFGT
    584* TLMETEFKKIFVLGPGAFGT
    585* TLMETEFKKIFVLGSGAFGT
    586* TLMETEFKKIKVLGPGAFGT
    587* TLMETEFKKIKVLGSGAFGT
    588* TLMETEFKKLFVLGPGAFGT
    589* TLMETEFKKLFVLGSGAFGT
    590* TLMETEFKKLKVLGPGAFGT
    591* TLMETEFKKLKVLGSGAFGT
    592* TLMETELKKIFVLGPGAFGT
    593* TLMETELKKIFVLGSGAFGT
    594* TLMETELKKIKVLGPGAFGT
    595* TLMETELKKIKVLGSGAFGT
    596* TLMETELKKLFVLGPGAFGT
    597* TLMETELKKLFVLGSGAFGT
    598* TLMETELKKLKVLGPGAFGT
    599* TLMETELKKLKVLGSGAFGT
    600  VKITDFGLAKLLGA
    601* VKITDFGRAKLLGA
    602  YLEDRRLVHRDLA
    603  KVKIPVAIKELREATSPKA
    604* KVKIPVAIKAPKA
    605* KVKIPVAIKAPTS
    606* KVKIPVAIKDPKA
    607* KVKIPVAIKELKA
    608* KVKIPVAIKEPKA
    609* KVKIPVAIKEQKA
    610* KVKIPVAIKESKA
    611* KVKIPVAIKEVPK
    612* KVKIPVAIKIPKA
    613* KVKIPVAIKSPKA
    614* KVKIPVAIKTPKA
    615* KIPVAIKEASPKA
    616* KIPVAIKEFSPKA
    617* KIPVAIKENSPKA
    618* KIPVAIKVASPKA
    619* KIPVAIKVPSPKA
    • Experiments Peptide Arrays
  • Peptide arrays were created by PepStar™ (JPT Peptide Technologies GmbH, Berlin, Germany) peptide microarray platform to generate customized peptide microarrays on glass slides for biomarker discovery, immunomonitoring and detection and validation of protein interactions. Peptides are immobilized on glass slides via a flexible linker. Chemoselective coupling generates microarrays of directed and covalently attached peptides.
  • 3661 specified native peptides with 500 scrambled control sequences covering the sequences of EGF-receptor, Arachidonate 15-lipoxygenase B (LX15B) and p53 and variants thereof were synthesized and arrays printed. A serum dilution 1:200 was used for the detection of EGFR binding in NSCLC patient samples. Incubation of microarrays was performed in an automated Hybridization Station HS4800 (Tecan) at 30° C. After washing, bound immunoglobine G (IgG) was detected with Cy5—labeled-anti-human secondary antibody (JIR, 0.1 μg/ml end-conc. in assay). Fluorescence was read using a Microarray Scanner GenePix with Autoloader 4200AL (Molecular Devices). Signal intensity is displayed as relative fluorescence units.
  • The following tables detail the wash and incubation conditions:
  • TABLE 5
    experimental conditions
    Blocking Solution: SmartBlock Blocking Buffer
    Diluent for Serum and 2nd AB: SuperBlock T20 Blocking Buffer
    Wash Buffer 1:   1x TBS + 0.1% Tween 20
    Wash Buffer 2: 0.1x SSC + 0.05% Tween 20
  • TABLE 6
    experimental conditions
    Step Procedure Parameters Buffer
     1 Wash 1x   1x TBS-0, 1% Tween20
     2 Probe injection 1 Blocking Solution
     3 Hybridization 1 h, 30° C.
     4 Wash 2x   1x TBS-0, 1% Tween20
     5 Probe injection 2 1:200 Patient Serum
     6 Hybridization 2 h, 30° C.
     7 Wash 3x   1x TBS-0, 1% Tween20
     8 Probe injection 3 Cy5-anti-human Secondary Antibody
     9 Hybridization 45 min.,
    30° C.
    10 Wash 2x   1x TBS-0, 1% Tween20
    11 Wash 3x 0.1x SSC-0.05% Tween20
    12 Slide drying 20 sec
    13 Wash 3x 0.1x SSC-0.05% Tween20
    14 Slide drying 5 min.
    • Samples
  • Samples were selected from patients belonging to the TASK study. TASK was a 200-patient randomized, open label, Phase II study of Tarceva® in combination with Avastin® (bevazizumab) compared to standard chemotherapy regimens (gemcitabine plus cisplatin or paclitaxel plus carboplatin) plus Avastin® in first-line NSCLC patients. Further enrollment on this study was halt after data from a pre-planned interim analysis of the first 120 patients. Occurrence of rash was recorded as adverse event. Biopsies from all patients were tested for the occurrence of EGFR mutations and the mutation status has been recorded.
  • For the peptide array study, a total of 49 patients from both arms (24 Avastin® and Tarceva® (A+T), 25 Avastin® and chemotherapy (A+C)) have been used. In the patients chosen for the A+T arm, rash occurred in 16 patients. In comparison, only 3 patients in the A+C arm developed rash. This corresponds to the expected frequency of rash, as rash is induced by erlotinib, but only to a very limited extend by chemotherapy.
  • Clinical data accessible included outcome data, e.g. response overall survival and progression free survival as well as the rash grade and the mutation status of EGFR as measured from a pre-treatment biopsy.
    • Statistical Analysis Global Test
  • The following approach to model the data was applied:
      • Descriptive statistics (using appropriate single variable) tests to identify covariates as candidates for a linear regression model describing the performance parameter (PFS or OS).
      • Identification of the best model for efficacy parameters (survival analysis)
      • Addition of antibody titer and its interaction with treatment to the model and comparison of the performance with the new variables
        With a general model selected, tests on antibody titers within groups of covariates of interest were conducted:
      • Proportional hazard model by EGFR mutation (EGFRM), Thoracic Radiotherapy (TRT), rash of efficacy parameters vs. antibody abundance (two sample groups—low/high abundance—divided by median)
      • U-tests within wild type (WT+) in A+T arm of antibody titer vs. responders/non-responders
      • χ2 tests by EGFRM and TRT of responses (weeks 6, 12) vs. antibody abundance
  • Finally, various very similar peptide sequences that yield highly correlated antibody titers were used. For most of the reported peptide sequences, consensus sequence from a listing of all peptides with very high sequence similarity (Smith-Waterman alignment similarity score >50, using a PAM30 substitution matrix and a gap penalty of 1) was selected and antibody titers were correlated to the target titer (Spearman Rank correlation >0.75).

Claims (40)

1. A method of diagnosis of non-small cell lung cancer in a human subject comprising:
measuring in a blood sample of the human subject a level of an autoantibody selected from the group of autoantibodies recognizing mutated human EGFR, wherein an increased level of said autoantibody selected from the group of autoantibodies recognizing mutated human EGFR in the blood sample of the human subject compared to a level of said autoantibody representative for a human subject of a healthy population is indicative for non-small cell lung cancer.
2. The method according to claim 1, wherein the autoantibody recognizes a mutated EGFR peptide is selected from the group consisting of Seq. Id. No. 554, Seq. Id. No. 555, Seq. Id. No. 556, Seq. Id. No. 557, Seq. Id. No. 558, Seq. Id. No. 559, and Seq. Id. No. 560.
3. The method according to any of claims 1-2, wherein the autoantibody recognizes a mutated EGFR peptide is selected from the group consisting of Seq. Id. No. 1, Seq. Id. No. 2, Seq. Id. No. 4, Seq. Id. No. 5, Seq. Id. No. 6, Seq. Id. No. 7, Seq. Id. No. 15, Seq. Id. No. 16, Seq. Id. No. 17, Seq. Id. No. 18, Seq. Id. No. 19, Seq. Id. No. 20, Seq. Id. No. 21, Seq. Id. No. 22, Seq. Id. No. 23, Seq. Id. No. 24, Seq. Id. No. 25, Seq. Id. No. 26, Seq. Id. No. 27, Seq. Id. No. 28, Seq. Id. No. 29, Seq. Id. No. 30, Seq. Id. No. 31, Seq. Id. No. 32, Seq. Id. No. 33, Seq. Id. No. 34, Seq. Id. No. 35, Seq. Id. No. 36, Seq. Id. No. 37, Seq. Id. No. 38, Seq. Id. No. 39, Seq. Id. No. 40, Seq. Id. No. 41, Seq. Id. No. 42, Seq. Id. No. 43, Seq. Id. No. 44, Seq. Id. No. 45, Seq. Id. No. 46, Seq. Id. No. 47, Seq. Id. No. 48, Seq. Id. No. 49, Seq. Id. No. 50, Seq. Id. No. 51, Seq. Id. No. 52, Seq. Id. No. 53, Seq. Id. No. 54, Seq. Id. No. 55, Seq. Id. No. 56, Seq. Id. No. 57, Seq. Id. No. 58, Seq. Id. No. 59, Seq. Id. No. 60, Seq. Id. No. 61, Seq. Id. No. 62, Seq. Id. No. 63, Seq. Id. No. 65, Seq. Id. No. 66, Seq. Id. No. 67, Seq. Id. No. 68, Seq. Id. No. 69, Seq. Id. No. 70, Seq. Id. No. 71, Seq. Id. No. 72, Seq. Id. No. 73, Seq. Id. No. 74, Seq. Id. No. 75, Seq. Id. No. 76, Seq. Id. No. 77, Seq. Id. No. 78, Seq. Id. No. 79, Seq. Id. No. 80, Seq. Id. No. 81, Seq. Id. No. 82, Seq. Id. No. 83, Seq. Id. No. 84, Seq. Id. No. 85, Seq. Id. No. 86, Seq. Id. No. 87, Seq. Id. No. 88, Seq. Id. No. 89, Seq. Id. No. 90, Seq. Id. No. 91, Seq. Id. No. 92, Seq. Id. No. 93, Seq. Id. No. 94, Seq. Id. No. 95, Seq. Id. No. 96, Seq. Id. No. 97, Seq. Id. No. 98, Seq. Id. No. 99, Seq. Id. No. 100, Seq. Id. No. 101, Seq. Id. No. 103, Seq. Id. No. 104, Seq. Id. No. 105, Seq. Id. No. 106, Seq. Id. No. 107, Seq. Id. No. 108, Seq. Id. No. 109, Seq. Id. No. 110, Seq. Id. No. 111, Seq. Id. No. 112, Seq. Id. No. 113, Seq. Id. No. 114, Seq. Id. No. 115, Seq. Id. No. 116, Seq. Id. No. 117, Seq. Id. No. 118, Seq. Id. No. 119, Seq. Id. No. 120, Seq. Id. No. 121, Seq. Id. No. 122, Seq. Id. No. 123, Seq. Id. No. 124, Seq. Id. No. 125, Seq. Id. No. 126, Seq. Id. No. 127, Seq. Id. No. 128, Seq. Id. No. 129, Seq. Id. No. 130, Seq. Id. No. 131, Seq. Id. No. 132, Seq. Id. No. 133, Seq. Id. No. 134, Seq. Id. No. 135, Seq. Id. No. 136, Seq. Id. No. 137, Seq. Id. No. 138, Seq. Id. No. 139, Seq. Id. No. 140, Seq. Id. No. 141, Seq. Id. No. 142, Seq. Id. No. 143, Seq. Id. No. 144, Seq. Id. No. 145, Seq. Id. No. 146, Seq. Id. No. 147, Seq. Id. No. 148, Seq. Id. No. 149, Seq. Id. No. 150, Seq. Id. No. 151, Seq. Id. No. 152, Seq. Id. No. 153, Seq. Id. No. 154, Seq. Id. No. 155, Seq. Id. No. 156, Seq. Id. No. 157, Seq. Id. No. 158, Seq. Id. No. 159, Seq. Id. No. 160, Seq. Id. No. 161, Seq. Id. No. 162, Seq. Id. No. 163, Seq. Id. No. 164, Seq. Id. No. 165, Seq. Id. No. 166, Seq. Id. No. 167, Seq. Id. No. 168, Seq. Id. No. 169, Seq. Id. No. 170, Seq. Id. No. 171, Seq. Id. No. 172, Seq. Id. No. 173, Seq. Id. No. 174, Seq. Id. No. 175, Seq. Id. No. 176, Seq. Id. No. 177, Seq. Id. No. 178, Seq. Id. No. 179, Seq. Id. No. 180, Seq. Id. No. 181, Seq. Id. No. 182, Seq. Id. No. 183, Seq. Id. No. 184, Seq. Id. No. 185, Seq. Id. No. 186, Seq. Id. No. 187, Seq. Id. No. 188, Seq. Id. No. 189, Seq. Id. No. 190, Seq. Id. No. 191, Seq. Id. No. 192, Seq. Id. No. 193, Seq. Id. No. 194, Seq. Id. No. 195, Seq. Id. No. 196, Seq. Id. No. 197, Seq. Id. No. 198, Seq. Id. No. 199, Seq. Id. No. 200, Seq. Id. No. 201, Seq. Id. No. 202, Seq. Id. No. 203, Seq. Id. No. 204, Seq. Id. No. 205, Seq. Id. No. 206, Seq. Id. No. 207, Seq. Id. No. 208, Seq. Id. No. 209, Seq. Id. No. 210, Seq. Id. No. 211, Seq. Id. No. 212, Seq. Id. No. 213, Seq. Id. No. 214, Seq. Id. No. 215, Seq. Id. No. 216, Seq. Id. No. 217, Seq. Id. No. 218, Seq. Id. No. 219, Seq. Id. No. 220, Seq. Id. No. 221, Seq. Id. No. 222, Seq. Id. No. 223, Seq. Id. No. 224, Seq. Id. No. 225, Seq. Id. No. 226, Seq. Id. No. 227, Seq. Id. No. 228, Seq. Id. No. 229, Seq. Id. No. 230, Seq. Id. No. 231, Seq. Id. No. 232, Seq. Id. No. 233, Seq. Id. No. 234, Seq. Id. No. 235, Seq. Id. No. 236, Seq. Id. No. 237, Seq. Id. No. 238, Seq. Id. No. 239, Seq. Id. No. 240, Seq. Id. No. 241, Seq. Id. No. 242, Seq. Id. No. 243, Seq. Id. No. 244, Seq. Id. No. 245, Seq. Id. No. 246, Seq. Id. No. 247, Seq. Id. No. 248, Seq. Id. No. 249, Seq. Id. No. 250, Seq. Id. No. 251, Seq. Id. No. 252, Seq. Id. No. 253, Seq. Id. No. 254, Seq. Id. No. 255, Seq. Id. No. 256, Seq. Id. No. 257, Seq. Id. No. 258, Seq. Id. No. 259, Seq. Id. No. 260, Seq. Id. No. 261, Seq. Id. No. 262, Seq. Id. No. 263, Seq. Id. No. 264, Seq. Id. No. 265, Seq. Id. No. 266, Seq. Id. No. 267, Seq. Id. No. 268, Seq. Id. No. 269, Seq. Id. No. 270, Seq. Id. No. 271, Seq. Id. No. 272, Seq. Id. No. 273, Seq. Id. No. 274, Seq. Id. No. 275, Seq. Id. No. 276, Seq. Id. No. 277, Seq. Id. No. 278, Seq. Id. No. 279, Seq. Id. No. 280, Seq. Id. No. 281, Seq. Id. No. 282, Seq. Id. No. 283, Seq. Id. No. 284, Seq. Id. No. 285, Seq. Id. No. 286, Seq. Id. No. 287, Seq. Id. No. 288, Seq. Id. No. 289, Seq. Id. No. 290, Seq. Id. No. 291, Seq. Id. No. 292, Seq. Id. No. 293, Seq. Id. No. 294, Seq. Id. No. 295, Seq. Id. No. 296, Seq. Id. No. 297, Seq. Id. No. 298, Seq. Id. No. 299, Seq. Id. No. 300, Seq. Id. No. 301, Seq. Id. No. 302, Seq. Id. No. 303, Seq. Id. No. 304, Seq. Id. No. 305, Seq. Id. No. 306, Seq. Id. No. 307, Seq. Id. No. 308, Seq. Id. No. 310, Seq. Id. No. 311, Seq. Id. No. 312, Seq. Id. No. 313, Seq. Id. No. 314, Seq. Id. No. 315, Seq. Id. No. 316, Seq. Id. No. 317, Seq. Id. No. 318, Seq. Id. No. 319, Seq. Id. No. 320, Seq. Id. No. 321, Seq. Id. No. 322, Seq. Id. No. 323, Seq. Id. No. 324, Seq. Id. No. 325, Seq. Id. No. 326, Seq. Id. No. 327, Seq. Id. No. 328, Seq. Id. No. 329, Seq. Id. No. 330, Seq. Id. No. 331, Seq. Id. No. 332, Seq. Id. No. 333, Seq. Id. No. 334, Seq. Id. No. 335, Seq. Id. No. 336, Seq. Id. No. 337, Seq. Id. No. 338, Seq. Id. No. 339, Seq. Id. No. 340, Seq. Id. No. 341, Seq. Id. No. 342, Seq. Id. No. 343, Seq. Id. No. 344, Seq. Id. No. 345, Seq. Id. No. 346, Seq. Id. No. 347, Seq. Id. No. 348, Seq. Id. No. 349, Seq. Id. No. 350, Seq. Id. No. 351, Seq. Id. No. 352, Seq. Id. No. 353, Seq. Id. No. 354, Seq. Id. No. 355, Seq. Id. No. 356, Seq. Id. No. 357, Seq. Id. No. 358, Seq. Id. No. 359, Seq. Id. No. 360, Seq. Id. No. 361, Seq. Id. No. 362, Seq. Id. No. 363, Seq. Id. No. 364, Seq. Id. No. 365, Seq. Id. No. 366, Seq. Id. No. 367, Seq. Id. No. 368, Seq. Id. No. 369, Seq. Id. No. 371, Seq. Id. No. 372, Seq. Id. No. 374, Seq. Id. No. 375, Seq. Id. No. 376, Seq. Id. No. 377, Seq. Id. No. 378, Seq. Id. No. 379, Seq. Id. No. 380, Seq. Id. No. 381, Seq. Id. No. 382, Seq. Id. No. 383, Seq. Id. No. 384, Seq. Id. No. 385, Seq. Id. No. 386, Seq. Id. No. 387, Seq. Id. No. 388, Seq. Id. No. 389, Seq. Id. No. 390, Seq. Id. No. 391, Seq. Id. No. 392, Seq. Id. No. 393, Seq. Id. No. 394, Seq. Id. No. 395, Seq. Id. No. 396, Seq. Id. No. 397, Seq. Id. No. 398, Seq. Id. No. 399, Seq. Id. No. 400, Seq. Id. No. 401, Seq. Id. No. 402, Seq. Id. No. 403, Seq. Id. No. 404, Seq. Id. No. 405, Seq. Id. No. 406, Seq. Id. No. 407, Seq. Id. No. 408, Seq. Id. No. 409, Seq. Id. No. 410, Seq. Id. No. 411, Seq. Id. No. 412, Seq. Id. No. 413, Seq. Id. No. 414, Seq. Id. No. 415, Seq. Id. No. 416, Seq. Id. No. 417, Seq. Id. No. 418, Seq. Id. No. 419, Seq. Id. No. 420, Seq. Id. No. 421, Seq. Id. No. 422, Seq. Id. No. 423, Seq. Id. No. 424, Seq. Id. No. 425, Seq. Id. No. 426, Seq. Id. No. 427, Seq. Id. No. 428, Seq. Id. No. 429, Seq. Id. No. 430, Seq. Id. No. 431, Seq. Id. No. 432, Seq. Id. No. 433, Seq. Id. No. 434, Seq. Id. No. 435, Seq. Id. No. 436, Seq. Id. No. 437, Seq. Id. No. 438, Seq. Id. No. 439, Seq. Id. No. 440, Seq. Id. No. 441, Seq. Id. No. 442, Seq. Id. No. 443, Seq. Id. No. 444, Seq. Id. No. 445, Seq. Id. No. 446, Seq. Id. No. 447, Seq. Id. No. 448, Seq. Id. No. 449, Seq. Id. No. 450, Seq. Id. No. 451, Seq. Id. No. 452, Seq. Id. No. 453, Seq. Id. No. 454, Seq. Id. No. 455, Seq. Id. No. 456, Seq. Id. No. 457, Seq. Id. No. 458, Seq. Id. No. 459, Seq. Id. No. 460, Seq. Id. No. 461, Seq. Id. No. 462, Seq. Id. No. 463, Seq. Id. No. 464, Seq. Id. No. 465, Seq. Id. No. 466, Seq. Id. No. 467, Seq. Id. No. 468, Seq. Id. No. 469, Seq. Id. No. 470, Seq. Id. No. 471, Seq. Id. No. 472, Seq. Id. No. 473, Seq. Id. No. 474, Seq. Id. No. 475, Seq. Id. No. 476, Seq. Id. No. 477, Seq. Id. No. 478, Seq. Id. No. 479, Seq. Id. No. 480, Seq. Id. No. 481, Seq. Id. No. 482, Seq. Id. No. 483, Seq. Id. No. 484, Seq. Id. No. 485, Seq. Id. No. 486, Seq. Id. No. 487, Seq. Id. No. 488, Seq. Id. No. 489, Seq. Id. No. 490, Seq. Id. No. 491, Seq. Id. No. 492, Seq. Id. No. 493, Seq. Id. No. 494, Seq. Id. No. 495, Seq. Id. No. 496, Seq. Id. No. 497, Seq. Id. No. 498, Seq. Id. No. 499, Seq. Id. No. 500, Seq. Id. No. 501, Seq. Id. No. 502, Seq. Id. No. 503, Seq. Id. No. 504, Seq. Id. No. 505, Seq. Id. No. 506, Seq. Id. No. 507, Seq. Id. No. 508, Seq. Id. No. 509, Seq. Id. No. 510, Seq. Id. No. 511, Seq. Id. No. 512, Seq. Id. No. 513, Seq. Id. No. 514, Seq. Id. No. 515, Seq. Id. No. 516, Seq. Id. No. 517, Seq. Id. No. 518, Seq. Id. No. 522, Seq. Id. No. 523, Seq. Id. No. 524, Seq. Id. No. 526, Seq. Id. No. 527, Seq. Id. No. 528, Seq. Id. No. 529, Seq. Id. No. 530, Seq. Id. No. 531, Seq. Id. No. 532, Seq. Id. No. 533, Seq. Id. No. 534, Seq. Id. No. 535, Seq. Id. No. 536, Seq. Id. No. 537, Seq. Id. No. 538, Seq. Id. No. 539, Seq. Id. No. 540, Seq. Id. No. 541, Seq. Id. No. 542, Seq. Id. No. 543, Seq. Id. No. 544, Seq. Id. No. 545, Seq. Id. No. 546, Seq. Id. No. 547, Seq. Id. No. 548, Seq. Id. No. 549, Seq. Id. No. 550, Seq. Id. No. 551, Seq. Id. No. 552, Seq. Id. No. 553, Seq. Id. No. 554, Seq. Id. No. 555, Seq. Id. No. 557, Seq. Id. No. 559, Seq. Id. No. 560, Seq. Id. No. 562, Seq. Id. No. 563, Seq. Id. No. 564, Seq. Id. No. 565, Seq. Id. No. 567, Seq. Id. No. 568, Seq. Id. No. 569, Seq. Id. No. 570, Seq. Id. No. 571, Seq. Id. No. 572, Seq. Id. No. 573, Seq. Id. No. 574, Seq. Id. No. 575, Seq. Id. No. 576, Seq. Id. No. 577, Seq. Id. No. 578, Seq. Id. No. 579, Seq. Id. No. 580, Seq. Id. No. 581, Seq. Id. No. 582, Seq. Id. No. 583, Seq. Id. No. 584, Seq. Id. No. 585, Seq. Id. No. 586, Seq. Id. No. 587, Seq. Id. No. 588, Seq. Id. No. 589, Seq. Id. No. 590, Seq. Id. No. 591, Seq. Id. No. 592, Seq. Id. No. 593, Seq. Id. No. 594, Seq. Id. No. 595, Seq. Id. No. 596, Seq. Id. No. 597, Seq. Id. No. 598, Seq. Id. No. 599, Seq. Id. No. 601, Seq. Id. No. 604, Seq. Id. No. 605, Seq. Id. No. 606, Seq. Id. No. 607, Seq. Id. No. 608, Seq. Id. No. 609, Seq. Id. No. 610, Seq. Id. No. 611, Seq. Id. No. 612, Seq. Id. No. 613, Seq. Id. No. 614, Seq. Id. No. 615, Seq. Id. No. 616, Seq. Id. No. 617, Seq. Id. No. 618 and Seq. Id. No. 619.
4. The method according to any of claims 1-3, wherein the autoantibody recognizes a mutated EGFR peptide that is selected from the groups consisting of Seq. Id. No. 1, Seq. Id. No. 2, Seq. Id. No. 4, Seq. Id. No. 5, Seq. Id. No. 6, Seq. Id. No. 7 and Seq. Id. No. 15.
5. The method according to any of claims 1-3, wherein the autoantibody recognizes a mutated EGFR peptide that is selected from the group consisting of Seq. Id. No. 16, Seq. Id. No. 17, Seq. Id. No. 18, Seq. Id. No. 19, Seq. Id. No. 20, Seq. Id. No. 21, Seq. Id. No. 22, Seq. Id. No. 23, Seq. Id. No. 24, Seq. Id. No. 25, Seq. Id. No. 26, Seq. Id. No. 27, Seq. Id. No. 28, Seq. Id. No. 29, Seq. Id. No. 30, Seq. Id. No. 31, Seq. Id. No. 32, Seq. Id. No. 33, Seq. Id. No. 34, Seq. Id. No. 35, Seq. Id. No. 36, Seq. Id. No. 37, Seq. Id. No. 38, Seq. Id. No. 39, Seq. Id. No. 40, Seq. Id. No. 41, Seq. Id. No. 42, Seq. Id. No. 43, Seq. Id. No. 44, Seq. Id. No. 45, Seq. Id. No. 46, Seq. Id. No. 47, Seq. Id. No. 48, Seq. Id. No. 49, Seq. Id. No. 50, Seq. Id. No. 51, Seq. Id. No. 52, Seq. Id. No. 53, Seq. Id. No. 54, Seq. Id. No. 55, Seq. Id. No. 56, Seq. Id. No. 57, Seq. Id. No. 58, Seq. Id. No. 59, Seq. Id. No. 60, Seq. Id. No. 61, Seq. Id. No. 62, Seq. Id. No. 63, Seq. Id. No. 65, Seq. Id. No. 66, Seq. Id. No. 67, Seq. Id. No. 68, Seq. Id. No. 69, Seq. Id. No. 70, Seq. Id. No. 71, Seq. Id. No. 72, Seq. Id. No. 73, Seq. Id. No. 74, Seq. Id. No. 75, Seq. Id. No. 76, Seq. Id. No. 77, Seq. Id. No. 78, Seq. Id. No. 79, Seq. Id. No. 80, Seq. Id. No. 81, Seq. Id. No. 82, Seq. Id. No. 83, Seq. Id. No. 84, Seq. Id. No. 85, Seq. Id. No. 86, Seq. Id. No. 87, Seq. Id. No. 88, Seq. Id. No. 89, Seq. Id. No. 90, Seq. Id. No. 91, Seq. Id. No. 92, Seq. Id. No. 93, Seq. Id. No. 94, Seq. Id. No. 95, Seq. Id. No. 96, Seq. Id. No. 97, Seq. Id. No. 98, Seq. Id. No. 99, Seq. Id. No. 100, Seq. Id. No. 101, Seq. Id. No. 103, Seq. Id. No. 104, Seq. Id. No. 105, Seq. Id. No. 106, Seq. Id. No. 107, Seq. Id. No. 108, Seq. Id. No. 109, Seq. Id. No. 110, Seq. Id. No. 111, Seq. Id. No. 112, Seq. Id. No. 113, Seq. Id. No. 114, Seq. Id. No. 115, Seq. Id. No. 116, Seq. Id. No. 117, Seq. Id. No. 118, Seq. Id. No. 119, Seq. Id. No. 120, Seq. Id. No. 121, Seq. Id. No. 122, Seq. Id. No. 123, Seq. Id. No. 124, Seq. Id. No. 125, Seq. Id. No. 126, Seq. Id. No. 127, Seq. Id. No. 128, Seq. Id. No. 129, Seq. Id. No. 130, Seq. Id. No. 131, Seq. Id. No. 132, Seq. Id. No. 133, Seq. Id. No. 134, Seq. Id. No. 135, Seq. Id. No. 136, Seq. Id. No. 137, Seq. Id. No. 138, Seq. Id. No. 139, Seq. Id. No. 140, Seq. Id. No. 141, Seq. Id. No. 142, Seq. Id. No. 143, Seq. Id. No. 144, Seq. Id. No. 145, Seq. Id. No. 146, Seq. Id. No. 147, Seq. Id. No. 148, Seq. Id. No. 149, Seq. Id. No. 150, Seq. Id. No. 151, Seq. Id. No. 152, Seq. Id. No. 153, Seq. Id. No. 154, Seq. Id. No. 155, Seq. Id. No. 156, Seq. Id. No. 157, Seq. Id. No. 158, Seq. Id. No. 159, Seq. Id. No. 160, Seq. Id. No. 161, Seq. Id. No. 162, Seq. Id. No. 163, Seq. Id. No. 164, Seq. Id. No. 165, Seq. Id. No. 166, Seq. Id. No. 167, Seq. Id. No. 168, Seq. Id. No. 169, Seq. Id. No. 170, Seq. Id. No. 171, Seq. Id. No. 172, Seq. Id. No. 173, Seq. Id. No. 174, Seq. Id. No. 175, Seq. Id. No. 176, Seq. Id. No. 177, Seq. Id. No. 178, Seq. Id. No. 179, Seq. Id. No. 180, Seq. Id. No. 181, Seq. Id. No. 182, Seq. Id. No. 183, Seq. Id. No. 184, Seq. Id. No. 185, Seq. Id. No. 186, Seq. Id. No. 187, Seq. Id. No. 188, Seq. Id. No. 189, Seq. Id. No. 190, Seq. Id. No. 191, Seq. Id. No. 192, Seq. Id. No. 193, Seq. Id. No. 194, Seq. Id. No. 195, Seq. Id. No. 196, Seq. Id. No. 197, Seq. Id. No. 198, Seq. Id. No. 199, Seq. Id. No. 200, Seq. Id. No. 201, Seq. Id. No. 202, Seq. Id. No. 203, Seq. Id. No. 204, Seq. Id. No. 205, Seq. Id. No. 206, Seq. Id. No. 207, Seq. Id. No. 208, Seq. Id. No. 209, Seq. Id. No. 210, Seq. Id. No. 211, Seq. Id. No. 212, Seq. Id. No. 213, Seq. Id. No. 214, Seq. Id. No. 215, Seq. Id. No. 216, Seq. Id. No. 217, Seq. Id. No. 218, Seq. Id. No. 219, Seq. Id. No. 220, Seq. Id. No. 221, Seq. Id. No. 222, Seq. Id. No. 223, Seq. Id. No. 224, Seq. Id. No. 225, Seq. Id. No. 226, Seq. Id. No. 227, Seq. Id. No. 228, Seq. Id. No. 229, Seq. Id. No. 230, Seq. Id. No. 231, Seq. Id. No. 232, Seq. Id. No. 233, Seq. Id. No. 234, Seq. Id. No. 235, Seq. Id. No. 236, Seq. Id. No. 237, Seq. Id. No. 238, Seq. Id. No. 239, Seq. Id. No. 240, Seq. Id. No. 241, Seq. Id. No. 242, Seq. Id. No. 243, Seq. Id. No. 244, Seq. Id. No. 245, Seq. Id. No. 246, Seq. Id. No. 247, Seq. Id. No. 248, Seq. Id. No. 249, Seq. Id. No. 250, Seq. Id. No. 251, Seq. Id. No. 252, Seq. Id. No. 253, Seq. Id. No. 254, Seq. Id. No. 255, Seq. Id. No. 256, Seq. Id. No. 257, Seq. Id. No. 258, Seq. Id. No. 259, Seq. Id. No. 260, Seq. Id. No. 261, Seq. Id. No. 262, Seq. Id. No. 263, Seq. Id. No. 264, Seq. Id. No. 265, Seq. Id. No. 266, Seq. Id. No. 267, Seq. Id. No. 268, Seq. Id. No. 269, Seq. Id. No. 270, Seq. Id. No. 271, Seq. Id. No. 272, Seq. Id. No. 273, Seq. Id. No. 274, Seq. Id. No. 275, Seq. Id. No. 276, Seq. Id. No. 277, Seq. Id. No. 278, Seq. Id. No. 279, Seq. Id. No. 280, Seq. Id. No. 281, Seq. Id. No. 282, Seq. Id. No. 283, Seq. Id. No. 284, Seq. Id. No. 285, Seq. Id. No. 286, Seq. Id. No. 287, Seq. Id. No. 288, Seq. Id. No. 289, Seq. Id. No. 290, Seq. Id. No. 291, Seq. Id. No. 292, Seq. Id. No. 293, Seq. Id. No. 294, Seq. Id. No. 295, Seq. Id. No. 296, Seq. Id. No. 297, Seq. Id. No. 298, Seq. Id. No. 299, Seq. Id. No. 300, Seq. Id. No. 301, Seq. Id. No. 302, Seq. Id. No. 303, Seq. Id. No. 304, Seq. Id. No. 305, Seq. Id. No. 306, Seq. Id. No. 307, Seq. Id. No. 308, Seq. Id. No. 310, Seq. Id. No. 311, Seq. Id. No. 312, Seq. Id. No. 313, Seq. Id. No. 314, Seq. Id. No. 315, Seq. Id. No. 316, Seq. Id. No. 317, Seq. Id. No. 318, Seq. Id. No. 319, Seq. Id. No. 320, Seq. Id. No. 321, Seq. Id. No. 322, Seq. Id. No. 323, Seq. Id. No. 324, Seq. Id. No. 325, Seq. Id. No. 326, Seq. Id. No. 327, Seq. Id. No. 328, Seq. Id. No. 329, Seq. Id. No. 330, Seq. Id. No. 331, Seq. Id. No. 332, Seq. Id. No. 333, Seq. Id. No. 334, Seq. Id. No. 335, Seq. Id. No. 336, Seq. Id. No. 337, Seq. Id. No. 338, Seq. Id. No. 339, Seq. Id. No. 340, Seq. Id. No. 341, Seq. Id. No. 342, Seq. Id. No. 343, Seq. Id. No. 344, Seq. Id. No. 345, Seq. Id. No. 346, Seq. Id. No. 347, Seq. Id. No. 348, Seq. Id. No. 349, Seq. Id. No. 350, Seq. Id. No. 351, Seq. Id. No. 352, Seq. Id. No. 353, Seq. Id. No. 354, Seq. Id. No. 355, Seq. Id. No. 356, Seq. Id. No. 357, Seq. Id. No. 358, Seq. Id. No. 359, Seq. Id. No. 360, Seq. Id. No. 361, Seq. Id. No. 362, Seq. Id. No. 363, Seq. Id. No. 364, Seq. Id. No. 365, Seq. Id. No. 366, Seq. Id. No. 367, Seq. Id. No. 368, Seq. Id. No. 369, Seq. Id. No. 371, Seq. Id. No. 372, Seq. Id. No. 374, Seq. Id. No. 375, Seq. Id. No. 376, Seq. Id. No. 377, Seq. Id. No. 378, Seq. Id. No. 379, Seq. Id. No. 380, Seq. Id. No. 381, Seq. Id. No. 382, Seq. Id. No. 383, Seq. Id. No. 384, Seq. Id. No. 385, Seq. Id. No. 386, Seq. Id. No. 387, Seq. Id. No. 388, Seq. Id. No. 389, Seq. Id. No. 390, Seq. Id. No. 391, Seq. Id. No. 392, Seq. Id. No. 393, Seq. Id. No. 394, Seq. Id. No. 395, Seq. Id. No. 396, Seq. Id. No. 397, Seq. Id. No. 398, Seq. Id. No. 399, Seq. Id. No. 400, Seq. Id. No. 401, Seq. Id. No. 402, Seq. Id. No. 403, Seq. Id. No. 404, Seq. Id. No. 405, Seq. Id. No. 406, Seq. Id. No. 407, Seq. Id. No. 408, Seq. Id. No. 409, Seq. Id. No. 410, Seq. Id. No. 411, Seq. Id. No. 412, Seq. Id. No. 413, Seq. Id. No. 414, Seq. Id. No. 415, Seq. Id. No. 416, Seq. Id. No. 417, Seq. Id. No. 418, Seq. Id. No. 419, Seq. Id. No. 420, Seq. Id. No. 421, Seq. Id. No. 422, Seq. Id. No. 423, Seq. Id. No. 424, Seq. Id. No. 425, Seq. Id. No. 426, Seq. Id. No. 427, Seq. Id. No. 428, Seq. Id. No. 429, Seq. Id. No. 430, Seq. Id. No. 431, Seq. Id. No. 432, Seq. Id. No. 433, Seq. Id. No. 434, Seq. Id. No. 435, Seq. Id. No. 436, Seq. Id. No. 437, Seq. Id. No. 438, Seq. Id. No. 439, Seq. Id. No. 440, Seq. Id. No. 441, Seq. Id. No. 442, Seq. Id. No. 443, Seq. Id. No. 444, Seq. Id. No. 445, Seq. Id. No. 446, Seq. Id. No. 447, Seq. Id. No. 448, Seq. Id. No. 449, Seq. Id. No. 450, Seq. Id. No. 451, Seq. Id. No. 452, Seq. Id. No. 453, Seq. Id. No. 454, Seq. Id. No. 455, Seq. Id. No. 456, Seq. Id. No. 457, Seq. Id. No. 458, Seq. Id. No. 459, Seq. Id. No. 460, Seq. Id. No. 461, Seq. Id. No. 462, Seq. Id. No. 463, Seq. Id. No. 464, Seq. Id. No. 465, Seq. Id. No. 466, Seq. Id. No. 467, Seq. Id. No. 468, Seq. Id. No. 469, Seq. Id. No. 470, Seq. Id. No. 471, Seq. Id. No. 472, Seq. Id. No. 473, Seq. Id. No. 474, Seq. Id. No. 475, Seq. Id. No. 476, Seq. Id. No. 477, Seq. Id. No. 478, Seq. Id. No. 479, Seq. Id. No. 480, Seq. Id. No. 481, Seq. Id. No. 482, Seq. Id. No. 483, Seq. Id. No. 484, Seq. Id. No. 485, Seq. Id. No. 486, Seq. Id. No. 487, Seq. Id. No. 488, Seq. Id. No. 489, Seq. Id. No. 490, Seq. Id. No. 491, Seq. Id. No. 492, Seq. Id. No. 493, Seq. Id. No. 494, Seq. Id. No. 495, Seq. Id. No. 496, Seq. Id. No. 497, Seq. Id. No. 498, Seq. Id. No. 499, Seq. Id. No. 500, Seq. Id. No. 501, Seq. Id. No. 502, Seq. Id. No. 503, Seq. Id. No. 504, Seq. Id. No. 505, Seq. Id. No. 506, Seq. Id. No. 507, Seq. Id. No. 508, Seq. Id. No. 509, Seq. Id. No. 510, Seq. Id. No. 511, Seq. Id. No. 512, Seq. Id. No. 513, Seq. Id. No. 514, Seq. Id. No. 515, Seq. Id. No. 516 and Seq. Id. No. 517.
6. The method according to any of claims 1-3, wherein the autoantibody recognizes a mutated EGFR peptide that is selected from the group consisting of Seq. Id. No. 518, Seq. Id. No. 522, Seq. Id. No. 523, Seq. Id. No. 524, Seq. Id. No. 526, Seq. Id. No. 527, Seq. Id. No. 528, Seq. Id. No. 529, Seq. Id. No. 530, Seq. Id. No. 531, Seq. Id. No. 532, Seq. Id. No. 533, Seq. Id. No. 534, Seq. Id. No. 535, Seq. Id. No. 536, Seq. Id. No. 537, Seq. Id. No. 538, Seq. Id. No. 539, Seq. Id. No. 540, Seq. Id. No. 541, Seq. Id. No. 542, Seq. Id. No. 543, Seq. Id. No. 544, Seq. Id. No. 545, Seq. Id. No. 546, Seq. Id. No. 547, Seq. Id. No. 548, Seq. Id. No. 549, Seq. Id. No. 550, Seq. Id. No. 551, Seq. Id. No. 552, Seq. Id. No. 553, Seq. Id. No. 554, Seq. Id. No. 555, Seq. Id. No. 557, Seq. Id. No. 559, Seq. Id. No. 560, Seq. Id. No. 562, Seq. Id. No. 563, Seq. Id. No. 564, Seq. Id. No. 565, Seq. Id. No. 567, Seq. Id. No. 568, Seq. Id. No. 569, Seq. Id. No. 570, Seq. Id. No. 571, Seq. Id. No. 572, Seq. Id. No. 573, Seq. Id. No. 574, Seq. Id. No. 575, Seq. Id. No. 576, Seq. Id. No. 577, Seq. Id. No. 578, Seq. Id. No. 579, Seq. Id. No. 580, Seq. Id. No. 581, Seq. Id. No. 582, Seq. Id. No. 583, Seq. Id. No. 584, Seq. Id. No. 585, Seq. Id. No. 586, Seq. Id. No. 587, Seq. Id. No. 588, Seq. Id. No. 589, Seq. Id. No. 590, Seq. Id. No. 591, Seq. Id. No. 592, Seq. Id. No. 593, Seq. Id. No. 594, Seq. Id. No. 595, Seq. Id. No. 596, Seq. Id. No. 597, Seq. Id. No. 598, Seq. Id. No. 599 and Seq. Id. No. 601.
7. The method according to any of claims 1-3, wherein the autoantibody recognizes a mutated EGFR peptide that is selected from the group consisting of Seq. Id. No. 604, Seq. Id. No. 605, Seq. Id. No. 606, Seq. Id. No. 607, Seq. Id. No. 608, Seq. Id. No. 609, Seq. Id. No. 610, Seq. Id. No. 611, Seq. Id. No. 612, Seq. Id. No. 613, Seq. Id. No. 614, Seq. Id. No. 615, Seq. Id. No. 616, Seq. Id. No. 617, Seq. Id. No. 618 and Seq. Id. No. 619.
8. The method according to any of claims 1-7, wherein the level of an autoantibody in the blood sample of the human subject is 5 times higher than the level of said autoantibody representative for a human subject of a healthy population.
9. Erlotinib or a pharmaceutically acceptable salt thereof, in particular erlotinib hydrochloride, for use in treating a NSCLC patient identified by a method of any of claims 1 to 8 comprising administering erlotinib or a pharmaceutically acceptable salt thereof, in particular erlotinib hydrochloride to the patient.
10. Use of an autoantibody for predicting the response of a NSCLC patient to erlotinib or a pharmaceutically acceptable salt thereof, in particular erlotinib hydrochloride, treatment, which antibody was identified by a method of any of claims 1 to 8.
11. A kit for detecting in a blood sample of the human subject a level of one or more autoantibodies selected from the group of autoantibodies recognizing mutated human EGFR, wherein an increased level of said autoantibodies selected from the group of autoantibodies recognizing mutated human EGFR in the blood sample of the human subject compared to a level of said autoantibodies representative for a human subject of a healthy population is indicative for non-small cell lung cancer.
12. A kit according to claim 11, wherein the autoantibody recognizes a mutated EGFR peptide that is selected from the group consisting of Seq. Id. No. 554, Seq. Id. No. 555, Seq. Id. No. 556, Seq. Id. No. 557, Seq. Id. No. 558, Seq. Id. No. 559, and Seq. Id. No. 560.
13. A kit according to claim 11, wherein the autoantibody recognizes a mutated EGFR peptide that is selected from the group consisting of Seq. Id. No. 1, Seq. Id. No. 2, Seq. Id. No. 4, Seq. Id. No. 5, Seq. Id. No. 6, Seq. Id. No. 7 and Seq. Id. No. 15.
14. A kit according to claim 11, wherein the autoantibody recognizes a mutated EGFR peptide that is selected from the group consisting of Seq. Id. No. 16, Seq. Id. No. 17, Seq. Id. No. 18, Seq. Id. No. 19, Seq. Id. No. 20, Seq. Id. No. 21, Seq. Id. No. 22, Seq. Id. No. 23, Seq. Id. No. 24, Seq. Id. No. 25, Seq. Id. No. 26, Seq. Id. No. 27, Seq. Id. No. 28, Seq. Id. No. 29, Seq. Id. No. 30, Seq. Id. No. 31, Seq. Id. No. 32, Seq. Id. No. 33, Seq. Id. No. 34, Seq. Id. No. 35, Seq. Id. No. 36, Seq. Id. No. 37, Seq. Id. No. 38, Seq. Id. No. 39, Seq. Id. No. 40, Seq. Id. No. 41, Seq. Id. No. 42, Seq. Id. No. 43, Seq. Id. No. 44, Seq. Id. No. 45, Seq. Id. No. 46, Seq. Id. No. 47, Seq. Id. No. 48, Seq. Id. No. 49, Seq. Id. No. 50, Seq. Id. No. 51, Seq. Id. No. 52, Seq. Id. No. 53, Seq. Id. No. 54, Seq. Id. No. 55, Seq. Id. No. 56, Seq. Id. No. 57, Seq. Id. No. 58, Seq. Id. No. 59, Seq. Id. No. 60, Seq. Id. No. 61, Seq. Id. No. 62, Seq. Id. No. 63, Seq. Id. No. 65, Seq. Id. No. 66, Seq. Id. No. 67, Seq. Id. No. 68, Seq. Id. No. 69, Seq. Id. No. 70, Seq. Id. No. 71, Seq. Id. No. 72, Seq. Id. No. 73, Seq. Id. No. 74, Seq. Id. No. 75, Seq. Id. No. 76, Seq. Id. No. 77, Seq. Id. No. 78, Seq. Id. No. 79, Seq. Id. No. 80, Seq. Id. No. 81, Seq. Id. No. 82, Seq. Id. No. 83, Seq. Id. No. 84, Seq. Id. No. 85, Seq. Id. No. 86, Seq. Id. No. 87, Seq. Id. No. 88, Seq. Id. No. 89, Seq. Id. No. 90, Seq. Id. No. 91, Seq. Id. No. 92, Seq. Id. No. 93, Seq. Id. No. 94, Seq. Id. No. 95, Seq. Id. No. 96, Seq. Id. No. 97, Seq. Id. No. 98, Seq. Id. No. 99, Seq. Id. No. 100, Seq. Id. No. 101, Seq. Id. No. 103, Seq. Id. No. 104, Seq. Id. No. 105, Seq. Id. No. 106, Seq. Id. No. 107, Seq. Id. No. 108, Seq. Id. No. 109, Seq. Id. No. 110, Seq. Id. No. 111, Seq. Id. No. 112, Seq. Id. No. 113, Seq. Id. No. 114, Seq. Id. No. 115, Seq. Id. No. 116, Seq. Id. No. 117, Seq. Id. No. 118, Seq. Id. No. 119, Seq. Id. No. 120, Seq. Id. No. 121, Seq. Id. No. 122, Seq. Id. No. 123, Seq. Id. No. 124, Seq. Id. No. 125, Seq. Id. No. 126, Seq. Id. No. 127, Seq. Id. No. 128, Seq. Id. No. 129, Seq. Id. No. 130, Seq. Id. No. 131, Seq. Id. No. 132, Seq. Id. No. 133, Seq. Id. No. 134, Seq. Id. No. 135, Seq. Id. No. 136, Seq. Id. No. 137, Seq. Id. No. 138, Seq. Id. No. 139, Seq. Id. No. 140, Seq. Id. No. 141, Seq. Id. No. 142, Seq. Id. No. 143, Seq. Id. No. 144, Seq. Id. No. 145, Seq. Id. No. 146, Seq. Id. No. 147, Seq. Id. No. 148, Seq. Id. No. 149, Seq. Id. No. 150, Seq. Id. No. 151, Seq. Id. No. 152, Seq. Id. No. 153, Seq. Id. No. 154, Seq. Id. No. 155, Seq. Id. No. 156, Seq. Id. No. 157, Seq. Id. No. 158, Seq. Id. No. 159, Seq. Id. No. 160, Seq. Id. No. 161, Seq. Id. No. 162, Seq. Id. No. 163, Seq. Id. No. 164, Seq. Id. No. 165, Seq. Id. No. 166, Seq. Id. No. 167, Seq. Id. No. 168, Seq. Id. No. 169, Seq. Id. No. 170, Seq. Id. No. 171, Seq. Id. No. 172, Seq. Id. No. 173, Seq. Id. No. 174, Seq. Id. No. 175, Seq. Id. No. 176, Seq. Id. No. 177, Seq. Id. No. 178, Seq. Id. No. 179, Seq. Id. No. 180, Seq. Id. No. 181, Seq. Id. No. 182, Seq. Id. No. 183, Seq. Id. No. 184, Seq. Id. No. 185, Seq. Id. No. 186, Seq. Id. No. 187, Seq. Id. No. 188, Seq. Id. No. 189, Seq. Id. No. 190, Seq. Id. No. 191, Seq. Id. No. 192, Seq. Id. No. 193, Seq. Id. No. 194, Seq. Id. No. 195, Seq. Id. No. 196, Seq. Id. No. 197, Seq. Id. No. 198, Seq. Id. No. 199, Seq. Id. No. 200, Seq. Id. No. 201, Seq. Id. No. 202, Seq. Id. No. 203, Seq. Id. No. 204, Seq. Id. No. 205, Seq. Id. No. 206, Seq. Id. No. 207, Seq. Id. No. 208, Seq. Id. No. 209, Seq. Id. No. 210, Seq. Id. No. 211, Seq. Id. No. 212, Seq. Id. No. 213, Seq. Id. No. 214, Seq. Id. No. 215, Seq. Id. No. 216, Seq. Id. No. 217, Seq. Id. No. 218, Seq. Id. No. 219, Seq. Id. No. 220, Seq. Id. No. 221, Seq. Id. No. 222, Seq. Id. No. 223, Seq. Id. No. 224, Seq. Id. No. 225, Seq. Id. No. 226, Seq. Id. No. 227, Seq. Id. No. 228, Seq. Id. No. 229, Seq. Id. No. 230, Seq. Id. No. 231, Seq. Id. No. 232, Seq. Id. No. 233, Seq. Id. No. 234, Seq. Id. No. 235, Seq. Id. No. 236, Seq. Id. No. 237, Seq. Id. No. 238, Seq. Id. No. 239, Seq. Id. No. 240, Seq. Id. No. 241, Seq. Id. No. 242, Seq. Id. No. 243, Seq. Id. No. 244, Seq. Id. No. 245, Seq. Id. No. 246, Seq. Id. No. 247, Seq. Id. No. 248, Seq. Id. No. 249, Seq. Id. No. 250, Seq. Id. No. 251, Seq. Id. No. 252, Seq. Id. No. 253, Seq. Id. No. 254, Seq. Id. No. 255, Seq. Id. No. 256, Seq. Id. No. 257, Seq. Id. No. 258, Seq. Id. No. 259, Seq. Id. No. 260, Seq. Id. No. 261, Seq. Id. No. 262, Seq. Id. No. 263, Seq. Id. No. 264, Seq. Id. No. 265, Seq. Id. No. 266, Seq. Id. No. 267, Seq. Id. No. 268, Seq. Id. No. 269, Seq. Id. No. 270, Seq. Id. No. 271, Seq. Id. No. 272, Seq. Id. No. 273, Seq. Id. No. 274, Seq. Id. No. 275, Seq. Id. No. 276, Seq. Id. No. 277, Seq. Id. No. 278, Seq. Id. No. 279, Seq. Id. No. 280, Seq. Id. No. 281, Seq. Id. No. 282, Seq. Id. No. 283, Seq. Id. No. 284, Seq. Id. No. 285, Seq. Id. No. 286, Seq. Id. No. 287, Seq. Id. No. 288, Seq. Id. No. 289, Seq. Id. No. 290, Seq. Id. No. 291, Seq. Id. No. 292, Seq. Id. No. 293, Seq. Id. No. 294, Seq. Id. No. 295, Seq. Id. No. 296, Seq. Id. No. 297, Seq. Id. No. 298, Seq. Id. No. 299, Seq. Id. No. 300, Seq. Id. No. 301, Seq. Id. No. 302, Seq. Id. No. 303, Seq. Id. No. 304, Seq. Id. No. 305, Seq. Id. No. 306, Seq. Id. No. 307, Seq. Id. No. 308, Seq. Id. No. 310, Seq. Id. No. 311, Seq. Id. No. 312, Seq. Id. No. 313, Seq. Id. No. 314, Seq. Id. No. 315, Seq. Id. No. 316, Seq. Id. No. 317, Seq. Id. No. 318, Seq. Id. No. 319, Seq. Id. No. 320, Seq. Id. No. 321, Seq. Id. No. 322, Seq. Id. No. 323, Seq. Id. No. 324, Seq. Id. No. 325, Seq. Id. No. 326, Seq. Id. No. 327, Seq. Id. No. 328, Seq. Id. No. 329, Seq. Id. No. 330, Seq. Id. No. 331, Seq. Id. No. 332, Seq. Id. No. 333, Seq. Id. No. 334, Seq. Id. No. 335, Seq. Id. No. 336, Seq. Id. No. 337, Seq. Id. No. 338, Seq. Id. No. 339, Seq. Id. No. 340, Seq. Id. No. 341, Seq. Id. No. 342, Seq. Id. No. 343, Seq. Id. No. 344, Seq. Id. No. 345, Seq. Id. No. 346, Seq. Id. No. 347, Seq. Id. No. 348, Seq. Id. No. 349, Seq. Id. No. 350, Seq. Id. No. 351, Seq. Id. No. 352, Seq. Id. No. 353, Seq. Id. No. 354, Seq. Id. No. 355, Seq. Id. No. 356, Seq. Id. No. 357, Seq. Id. No. 358, Seq. Id. No. 359, Seq. Id. No. 360, Seq. Id. No. 361, Seq. Id. No. 362, Seq. Id. No. 363, Seq. Id. No. 364, Seq. Id. No. 365, Seq. Id. No. 366, Seq. Id. No. 367, Seq. Id. No. 368, Seq. Id. No. 369, Seq. Id. No. 371, Seq. Id. No. 372, Seq. Id. No. 374, Seq. Id. No. 375, Seq. Id. No. 376, Seq. Id. No. 377, Seq. Id. No. 378, Seq. Id. No. 379, Seq. Id. No. 380, Seq. Id. No. 381, Seq. Id. No. 382, Seq. Id. No. 383, Seq. Id. No. 384, Seq. Id. No. 385, Seq. Id. No. 386, Seq. Id. No. 387, Seq. Id. No. 388, Seq. Id. No. 389, Seq. Id. No. 390, Seq. Id. No. 391, Seq. Id. No. 392, Seq. Id. No. 393, Seq. Id. No. 394, Seq. Id. No. 395, Seq. Id. No. 396, Seq. Id. No. 397, Seq. Id. No. 398, Seq. Id. No. 399, Seq. Id. No. 400, Seq. Id. No. 401, Seq. Id. No. 402, Seq. Id. No. 403, Seq. Id. No. 404, Seq. Id. No. 405, Seq. Id. No. 406, Seq. Id. No. 407, Seq. Id. No. 408, Seq. Id. No. 409, Seq. Id. No. 410, Seq. Id. No. 411, Seq. Id. No. 412, Seq. Id. No. 413, Seq. Id. No. 414, Seq. Id. No. 415, Seq. Id. No. 416, Seq. Id. No. 417, Seq. Id. No. 418, Seq. Id. No. 419, Seq. Id. No. 420, Seq. Id. No. 421, Seq. Id. No. 422, Seq. Id. No. 423, Seq. Id. No. 424, Seq. Id. No. 425, Seq. Id. No. 426, Seq. Id. No. 427, Seq. Id. No. 428, Seq. Id. No. 429, Seq. Id. No. 430, Seq. Id. No. 431, Seq. Id. No. 432, Seq. Id. No. 433, Seq. Id. No. 434, Seq. Id. No. 435, Seq. Id. No. 436, Seq. Id. No. 437, Seq. Id. No. 438, Seq. Id. No. 439, Seq. Id. No. 440, Seq. Id. No. 441, Seq. Id. No. 442, Seq. Id. No. 443, Seq. Id. No. 444, Seq. Id. No. 445, Seq. Id. No. 446, Seq. Id. No. 447, Seq. Id. No. 448, Seq. Id. No. 449, Seq. Id. No. 450, Seq. Id. No. 451, Seq. Id. No. 452, Seq. Id. No. 453, Seq. Id. No. 454, Seq. Id. No. 455, Seq. Id. No. 456, Seq. Id. No. 457, Seq. Id. No. 458, Seq. Id. No. 459, Seq. Id. No. 460, Seq. Id. No. 461, Seq. Id. No. 462, Seq. Id. No. 463, Seq. Id. No. 464, Seq. Id. No. 465, Seq. Id. No. 466, Seq. Id. No. 467, Seq. Id. No. 468, Seq. Id. No. 469, Seq. Id. No. 470, Seq. Id. No. 471, Seq. Id. No. 472, Seq. Id. No. 473, Seq. Id. No. 474, Seq. Id. No. 475, Seq. Id. No. 476, Seq. Id. No. 477, Seq. Id. No. 478, Seq. Id. No. 479, Seq. Id. No. 480, Seq. Id. No. 481, Seq. Id. No. 482, Seq. Id. No. 483, Seq. Id. No. 484, Seq. Id. No. 485, Seq. Id. No. 486, Seq. Id. No. 487, Seq. Id. No. 488, Seq. Id. No. 489, Seq. Id. No. 490, Seq. Id. No. 491, Seq. Id. No. 492, Seq. Id. No. 493, Seq. Id. No. 494, Seq. Id. No. 495, Seq. Id. No. 496, Seq. Id. No. 497, Seq. Id. No. 498, Seq. Id. No. 499, Seq. Id. No. 500, Seq. Id. No. 501, Seq. Id. No. 502, Seq. Id. No. 503, Seq. Id. No. 504, Seq. Id. No. 505, Seq. Id. No. 506, Seq. Id. No. 507, Seq. Id. No. 508, Seq. Id. No. 509, Seq. Id. No. 510, Seq. Id. No. 511, Seq. Id. No. 512, Seq. Id. No. 513, Seq. Id. No. 514, Seq. Id. No. 515, Seq. Id. No. 516 and Seq. Id. No. 517.
15. A kit according to claim 11, wherein the autoantibody recognizes a mutated EGFR peptide that is selected from the group consisting of Seq. Id. No. 518, Seq. Id. No. 522, Seq. Id. No. 523, Seq. Id. No. 524, Seq. Id. No. 526, Seq. Id. No. 527, Seq. Id. No. 528, Seq. Id. No. 529, Seq. Id. No. 530, Seq. Id. No. 531, Seq. Id. No. 532, Seq. Id. No. 533, Seq. Id. No. 534, Seq. Id. No. 535, Seq. Id. No. 536, Seq. Id. No. 537, Seq. Id. No. 538, Seq. Id. No. 539, Seq. Id. No. 540, Seq. Id. No. 541, Seq. Id. No. 542, Seq. Id. No. 543, Seq. Id. No. 544, Seq. Id. No. 545, Seq. Id. No. 546, Seq. Id. No. 547, Seq. Id. No. 548, Seq. Id. No. 549, Seq. Id. No. 550, Seq. Id. No. 551, Seq. Id. No. 552, Seq. Id. No. 553, Seq. Id. No. 554, Seq. Id. No. 555, Seq. Id. No. 557, Seq. Id. No. 559, Seq. Id. No. 560, Seq. Id. No. 562, Seq. Id. No. 563, Seq. Id. No. 564, Seq. Id. No. 565, Seq. Id. No. 567, Seq. Id. No. 568, Seq. Id. No. 569, Seq. Id. No. 570, Seq. Id. No. 571, Seq. Id. No. 572, Seq. Id. No. 573, Seq. Id. No. 574, Seq. Id. No. 575, Seq. Id. No. 576, Seq. Id. No. 577, Seq. Id. No. 578, Seq. Id. No. 579, Seq. Id. No. 580, Seq. Id. No. 581, Seq. Id. No. 582, Seq. Id. No. 583, Seq. Id. No. 584, Seq. Id. No. 585, Seq. Id. No. 586, Seq. Id. No. 587, Seq. Id. No. 588, Seq. Id. No. 589, Seq. Id. No. 590, Seq. Id. No. 591, Seq. Id. No. 592, Seq. Id. No. 593, Seq. Id. No. 594, Seq. Id. No. 595, Seq. Id. No. 596, Seq. Id. No. 597, Seq. Id. No. 598, Seq. Id. No. 599 and Seq. Id. No. 601.
16. A kit according to claim 11, wherein the autoantibody recognizes a mutated EGFR peptide that is selected from the group consisting of Seq. Id. No. 604, Seq. Id. No. 605, Seq. Id. No. 606, Seq. Id. No. 607, Seq. Id. No. 608, Seq. Id. No. 609, Seq. Id. No. 610, Seq. Id. No. 611, Seq. Id. No. 612, Seq. Id. No. 613, Seq. Id. No. 614, Seq. Id. No. 615, Seq. Id. No. 616, Seq. Id. No. 617, Seq. Id. No. 618 and Seq. Id. No. 619.
17. A method of diagnosis of non-small cell lung cancer in a human subject comprising:
measuring in a blood sample of the human subject a level of an autoantibody selected from the group of autoantibodies recognizing human EGFR, wherein an increased level of said autoantibody selected from the group of autoantibodies recognizing human EGFR in the blood sample of the human subject compared to a level of said autoantibody representative for a human subject of a healthy population is indicative for non-small cell lung cancer.
18. The method according to claim 16, wherein the autoantibody recognizes a mutated EGFR peptide is selected from the group consisting of Seq. Id. No. 519, Seq. Id. No. 520, Seq. Id. No. 521 and Seq. Id. No. 561.
19. The method according to any of claims 17-18, wherein the autoantibody recognizes an EGFR peptide is selected from the group consisting of Seq. Id. No. 1, Seq. Id. No. 2, Seq. Id. No. 3, Seq. Id. No. 4, Seq. Id. No. 5, Seq. Id. No. 6, Seq. Id. No. 7, Seq. Id. No. 8, Seq. Id. No. 9, Seq. Id. No. 10, Seq. Id. No. 11, Seq. Id. No. 12, Seq. Id. No. 13, Seq. Id. No. 14, Seq. Id. No. 15, Seq. Id. No. 16, Seq. Id. No. 17, Seq. Id. No. 18, Seq. Id. No. 19, Seq. Id. No. 20, Seq. Id. No. 21, Seq. Id. No. 22, Seq. Id. No. 23, Seq. Id. No. 24, Seq. Id. No. 25, Seq. Id. No. 26, Seq. Id. No. 27, Seq. Id. No. 28, Seq. Id. No. 29, Seq. Id. No. 30, Seq. Id. No. 31, Seq. Id. No. 32, Seq. Id. No. 33, Seq. Id. No. 34, Seq. Id. No. 35, Seq. Id. No. 36, Seq. Id. No. 37, Seq. Id. No. 38, Seq. Id. No. 39, Seq. Id. No. 40, Seq. Id. No. 41, Seq. Id. No. 42, Seq. Id. No. 43, Seq. Id. No. 44, Seq. Id. No. 45, Seq. Id. No. 46, Seq. Id. No. 47, Seq. Id. No. 48, Seq. Id. No. 49, Seq. Id. No. 50, Seq. Id. No. 51, Seq. Id. No. 52, Seq. Id. No. 53, Seq. Id. No. 54, Seq. Id. No. 55, Seq. Id. No. 56, Seq. Id. No. 57, Seq. Id. No. 58, Seq. Id. No. 59, Seq. Id. No. 60, Seq. Id. No. 61, Seq. Id. No. 62, Seq. Id. No. 63, Seq. Id. No. 64, Seq. Id. No. 65, Seq. Id. No. 66, Seq. Id. No. 67, Seq. Id. No. 68, Seq. Id. No. 69, Seq. Id. No. 70, Seq. Id. No. 71, Seq. Id. No. 72, Seq. Id. No. 73, Seq. Id. No. 74, Seq. Id. No. 75, Seq. Id. No. 76, Seq. Id. No. 77, Seq. Id. No. 78, Seq. Id. No. 79, Seq. Id. No. 80, Seq. Id. No. 81, Seq. Id. No. 82, Seq. Id. No. 83, Seq. Id. No. 84, Seq. Id. No. 85, Seq. Id. No. 86, Seq. Id. No. 87, Seq. Id. No. 88, Seq. Id. No. 89, Seq. Id. No. 90, Seq. Id. No. 91, Seq. Id. No. 92, Seq. Id. No. 93, Seq. Id. No. 94, Seq. Id. No. 95, Seq. Id. No. 96, Seq. Id. No. 97, Seq. Id. No. 98, Seq. Id. No. 99, Seq. Id. No. 100, Seq. Id. No. 101, Seq. Id. No. 102, Seq. Id. No. 103, Seq. Id. No. 104, Seq. Id. No. 105, Seq. Id. No. 106, Seq. Id. No. 107, Seq. Id. No. 108, Seq. Id. No. 109, Seq. Id. No. 110, Seq. Id. No. 111, Seq. Id. No. 112, Seq. Id. No. 113, Seq. Id. No. 114, Seq. Id. No. 115, Seq. Id. No. 116, Seq. Id. No. 117, Seq. Id. No. 118, Seq. Id. No. 119, Seq. Id. No. 120, Seq. Id. No. 121, Seq. Id. No. 122, Seq. Id. No. 123, Seq. Id. No. 124, Seq. Id. No. 125, Seq. Id. No. 126, Seq. Id. No. 127, Seq. Id. No. 128, Seq. Id. No. 129, Seq. Id. No. 130, Seq. Id. No. 131, Seq. Id. No. 132, Seq. Id. No. 133, Seq. Id. No. 134, Seq. Id. No. 135, Seq. Id. No. 136, Seq. Id. No. 137, Seq. Id. No. 138, Seq. Id. No. 139, Seq. Id. No. 140, Seq. Id. No. 141, Seq. Id. No. 142, Seq. Id. No. 143, Seq. Id. No. 144, Seq. Id. No. 145, Seq. Id. No. 146, Seq. Id. No. 147, Seq. Id. No. 148, Seq. Id. No. 149, Seq. Id. No. 150, Seq. Id. No. 151, Seq. Id. No. 152, Seq. Id. No. 153, Seq. Id. No. 154, Seq. Id. No. 155, Seq. Id. No. 156, Seq. Id. No. 157, Seq. Id. No. 158, Seq. Id. No. 159, Seq. Id. No. 160, Seq. Id. No. 161, Seq. Id. No. 162, Seq. Id. No. 163, Seq. Id. No. 164, Seq. Id. No. 165, Seq. Id. No. 166, Seq. Id. No. 167, Seq. Id. No. 168, Seq. Id. No. 169, Seq. Id. No. 170, Seq. Id. No. 171, Seq. Id. No. 172, Seq. Id. No. 173, Seq. Id. No. 174, Seq. Id. No. 175, Seq. Id. No. 176, Seq. Id. No. 177, Seq. Id. No. 178, Seq. Id. No. 179, Seq. Id. No. 180, Seq. Id. No. 181, Seq. Id. No. 182, Seq. Id. No. 183, Seq. Id. No. 184, Seq. Id. No. 185, Seq. Id. No. 186, Seq. Id. No. 187, Seq. Id. No. 188, Seq. Id. No. 189, Seq. Id. No. 190, Seq. Id. No. 191, Seq. Id. No. 192, Seq. Id. No. 193, Seq. Id. No. 194, Seq. Id. No. 195, Seq. Id. No. 196, Seq. Id. No. 197, Seq. Id. No. 198, Seq. Id. No. 199, Seq. Id. No. 200, Seq. Id. No. 201, Seq. Id. No. 202, Seq. Id. No. 203, Seq. Id. No. 204, Seq. Id. No. 205, Seq. Id. No. 206, Seq. Id. No. 207, Seq. Id. No. 208, Seq. Id. No. 209, Seq. Id. No. 210, Seq. Id. No. 211, Seq. Id. No. 212, Seq. Id. No. 213, Seq. Id. No. 214, Seq. Id. No. 215, Seq. Id. No. 216, Seq. Id. No. 217, Seq. Id. No. 218, Seq. Id. 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No. 274, Seq. Id. No. 275, Seq. Id. No. 276, Seq. Id. No. 277, Seq. Id. No. 278, Seq. Id. No. 279, Seq. Id. No. 280, Seq. Id. No. 281, Seq. Id. No. 282, Seq. Id. No. 283, Seq. Id. No. 284, Seq. Id. No. 285, Seq. Id. No. 286, Seq. Id. No. 287, Seq. Id. No. 288, Seq. Id. No. 289, Seq. Id. No. 290, Seq. Id. No. 291, Seq. Id. No. 292, Seq. Id. No. 293, Seq. Id. No. 294, Seq. Id. No. 295, Seq. Id. No. 296, Seq. Id. No. 297, Seq. Id. No. 298, Seq. Id. No. 299, Seq. Id. No. 300, Seq. Id. No. 301, Seq. Id. No. 302, Seq. Id. No. 303, Seq. Id. No. 304, Seq. Id. No. 305, Seq. Id. No. 306, Seq. Id. No. 307, Seq. Id. No. 308, Seq. Id. No. 309, Seq. Id. No. 310, Seq. Id. No. 311, Seq. Id. No. 312, Seq. Id. No. 313, Seq. Id. No. 314, Seq. Id. No. 315, Seq. Id. No. 316, Seq. Id. No. 317, Seq. Id. No. 318, Seq. Id. No. 319, Seq. Id. No. 320, Seq. Id. No. 321, Seq. Id. No. 322, Seq. Id. No. 323, Seq. Id. No. 324, Seq. Id. No. 325, Seq. Id. No. 326, Seq. Id. No. 327, Seq. Id. No. 328, Seq. Id. 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No. 549, Seq. Id. No. 550, Seq. Id. No. 551, Seq. Id. No. 552, Seq. Id. No. 553, Seq. Id. No. 554, Seq. Id. No. 555, Seq. Id. No. 556, Seq. Id. No. 557, Seq. Id. No. 558, Seq. Id. No. 559, Seq. Id. No. 560, Seq. Id. No. 561, Seq. Id. No. 562, Seq. Id. No. 563, Seq. Id. No. 564, Seq. Id. No. 565, Seq. Id. No. 566, Seq. Id. No. 567, Seq. Id. No. 568, Seq. Id. No. 569, Seq. Id. No. 570, Seq. Id. No. 571, Seq. Id. No. 572, Seq. Id. No. 573, Seq. Id. No. 574, Seq. Id. No. 575, Seq. Id. No. 576, Seq. Id. No. 577, Seq. Id. No. 578, Seq. Id. No. 579, Seq. Id. No. 580, Seq. Id. No. 581, Seq. Id. No. 582, Seq. Id. No. 583, Seq. Id. No. 584, Seq. Id. No. 585, Seq. Id. No. 586, Seq. Id. No. 587, Seq. Id. No. 588, Seq. Id. No. 589, Seq. Id. No. 590, Seq. Id. No. 591, Seq. Id. No. 592, Seq. Id. No. 593, Seq. Id. No. 594, Seq. Id. No. 595, Seq. Id. No. 596, Seq. Id. No. 597, Seq. Id. No. 598, Seq. Id. No. 599, Seq. Id. No. 600, Seq. Id. No. 601, Seq. Id. No. 602, Seq. Id. No. 603, Seq. Id. No. 604, Seq. Id. No. 605, Seq. Id. No. 606, Seq. Id. No. 607, Seq. Id. No. 608, Seq. Id. No. 609, Seq. Id. No. 610, Seq. Id. No. 611, Seq. Id. No. 612, Seq. Id. No. 613, Seq. Id. No. 614, Seq. Id. No. 615, Seq. Id. No. 616, Seq. Id. No. 617, Seq. Id. No. 618, and Seq. Id. No. 619.
20. The method according to any of claims 19, wherein the autoantibody recognizes an EGFR peptide that is selected from the group consisting of Seq. Id. No. 3, Seq. Id. No. 8, Seq. Id. No. 9, Seq. Id. No. 10, Seq. Id. No. 11, Seq. Id. No. 12, Seq. Id. No. 13, Seq. Id. No. 14, Seq. Id. No. 64, Seq. Id. No. 102, Seq. Id. No. 309, Seq. Id. No. 370, Seq. Id. No. 373, Seq. Id. No. 519, Seq. Id. No. 520, Seq. Id. No. 521, Seq. Id. No. 525, Seq. Id. No. 556, Seq. Id. No. 558, Seq. Id. No. 561, Seq. Id. No. 566, Seq. Id. No. 600, Seq. Id. No. 602 and Seq. Id. No. 603.
21. The method according to any of claims 17-20, wherein the level of an autoantibody in the blood sample of the human subject is 5 times higher than the level of said autoantibody representative for a human subject of a healthy population.
22. Erlotinib or a pharmaceutically acceptable salt thereof, in particular erlotinib hydrochloride, for use in treating a NSCLC patient identified by a method of any of claims 17 to 21 comprising administering erlotinib or a pharmaceutically acceptable salt thereof, in particular erlotinib hydrochloride to the patient.
23. Use of an autoantibody for predicting the response of a NSCLC patient to erlotinib or a pharmaceutically acceptable salt thereof, in particular erlotinib hydrochloride, treatment, which antibody was identified by a method of any of claims 17 to 21.
24. A kit for detecting in a blood sample of the human subject a level of one or more autoantibodies selected from the group of autoantibodies recognizing human EGFR, wherein an increased level of said autoantibodies selected from the group of autoantibodies recognizing human EGFR in the blood sample of the human subject compared to a level of said autoantibodies representative for a human subject of a healthy population is indicative for non-small cell lung cancer.
25. A kit according to claim 24, wherein the autoantibody recognizes an EGFR peptide that is selected from the group consisting of Seq. Id. No. 3, Seq. Id. No. 8, Seq. Id. No. 9, Seq. Id. No. 10, Seq. Id. No. 11, Seq. Id. No. 12, Seq. Id. No. 13, Seq. Id. No. 14, Seq. Id. No. 64, Seq. Id. No. 102, Seq. Id. No. 309, Seq. Id. No. 370, Seq. Id. No. 373, Seq. Id. No. 519, Seq. Id. No. 520, Seq. Id. No. 521, Seq. Id. No. 525, Seq. Id. No. 556, Seq. Id. No. 558, Seq. Id. No. 561, Seq. Id. No. 566, Seq. Id. No. 600, Seq. Id. No. 602 and Seq. Id. No. 603.
26. A kit according to claim 25, wherein the autoantibody recognizes an EGFR peptide that is selected from the group consisting of Seq. Id. No. 519, Seq. Id. No. 520, Seq. Id. No. 521, and Seq. Id. No. 561.
27. A method of diagnosis of non-small cell lung cancer in a human subject comprising:
a) measuring in a blood sample of the human subject a level of an autoantibody selected from the group of autoantibodies recognizing mutated human EGFR,
b) comparing the level of said autoantibody to a reference level, and
c) providing a diagnosis of non-small cell lung cancer when the level of said autoantibody is above the reference level.
28. A method of diagnosis of non-small cell lung cancer in a human subject comprising:
a) measuring in a blood sample of the human subject a level of an autoantibody selected from the group of autoantibodies recognizing mutated human EGFR,
b) comparing the level of said autoantibody to a reference level, and
c) recommending a treatment when the level of said autoantibody is above the reference level.
29. The method according to claim 27 or 28, wherein the autoantibody recognizes a mutated EGFR peptide is selected from the group consisting of Seq. Id. No. 554, Seq. Id. No. 555, Seq. Id. No. 556, Seq. Id. No. 557, Seq. Id. No. 558, Seq. Id. No. 559, and Seq. Id. No. 560.
30. The method according to any of claims 28-29, wherein the autoantibody recognizes a mutated EGFR peptide is selected from the group consisting of Seq. Id. No. 1, Seq. Id. No. 2, Seq. Id. No. 4, Seq. Id. No. 5, Seq. Id. No. 6, Seq. Id. No. 7, Seq. Id. No. 15, Seq. Id. No. 16, Seq. Id. No. 17, Seq. Id. No. 18, Seq. Id. No. 19, Seq. Id. No. 20, Seq. Id. No. 21, Seq. Id. No. 22, Seq. Id. No. 23, Seq. Id. No. 24, Seq. Id. No. 25, Seq. Id. No. 26, Seq. Id. No. 27, Seq. Id. No. 28, Seq. Id. No. 29, Seq. Id. No. 30, Seq. Id. No. 31, Seq. Id. No. 32, Seq. Id. No. 33, Seq. Id. No. 34, Seq. Id. No. 35, Seq. Id. No. 36, Seq. Id. No. 37, Seq. Id. No. 38, Seq. Id. No. 39, Seq. Id. No. 40, Seq. Id. No. 41, Seq. Id. No. 42, Seq. Id. No. 43, Seq. Id. No. 44, Seq. Id. No. 45, Seq. Id. No. 46, Seq. Id. No. 47, Seq. Id. No. 48, Seq. Id. No. 49, Seq. Id. No. 50, Seq. Id. No. 51, Seq. Id. No. 52, Seq. Id. No. 53, Seq. Id. No. 54, Seq. Id. No. 55, Seq. Id. No. 56, Seq. Id. No. 57, Seq. Id. No. 58, Seq. Id. No. 59, Seq. Id. No. 60, Seq. Id. No. 61, Seq. Id. No. 62, Seq. Id. No. 63, Seq. Id. No. 65, Seq. Id. No. 66, Seq. Id. No. 67, Seq. Id. No. 68, Seq. Id. No. 69, Seq. Id. No. 70, Seq. Id. No. 71, Seq. Id. No. 72, Seq. Id. No. 73, Seq. Id. No. 74, Seq. Id. No. 75, Seq. Id. No. 76, Seq. Id. No. 77, Seq. Id. No. 78, Seq. Id. No. 79, Seq. Id. No. 80, Seq. Id. No. 81, Seq. Id. No. 82, Seq. Id. No. 83, Seq. Id. No. 84, Seq. Id. No. 85, Seq. Id. No. 86, Seq. Id. No. 87, Seq. Id. No. 88, Seq. Id. No. 89, Seq. Id. No. 90, Seq. Id. No. 91, Seq. Id. No. 92, Seq. Id. No. 93, Seq. Id. No. 94, Seq. Id. No. 95, Seq. Id. No. 96, Seq. Id. No. 97, Seq. Id. No. 98, Seq. Id. No. 99, Seq. Id. No. 100, Seq. Id. No. 101, Seq. Id. No. 103, Seq. Id. No. 104, Seq. Id. No. 105, Seq. Id. No. 106, Seq. Id. No. 107, Seq. Id. No. 108, Seq. Id. No. 109, Seq. Id. No. 110, Seq. Id. No. 111, Seq. Id. No. 112, Seq. Id. No. 113, Seq. Id. No. 114, Seq. Id. No. 115, Seq. Id. No. 116, Seq. Id. No. 117, Seq. Id. 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31. The method according to any of claims 27-30, wherein the autoantibody recognizes a mutated EGFR peptide that is selected from the groups consisting of Seq. Id. No. 1, Seq. Id. No. 2, Seq. Id. No. 4, Seq. Id. No. 5, Seq. Id. No. 6, Seq. Id. No. 7 and Seq. Id. No. 15.
32. The method according to any of claims 27-30, wherein the autoantibody recognizes a mutated EGFR peptide that is selected from the group consisting of Seq. Id. No. 16, Seq. Id. No. 17, Seq. Id. No. 18, Seq. Id. No. 19, Seq. Id. No. 20, Seq. Id. No. 21, Seq. Id. No. 22, Seq. Id. No. 23, Seq. Id. No. 24, Seq. Id. No. 25, Seq. Id. No. 26, Seq. Id. No. 27, Seq. Id. No. 28, Seq. Id. No. 29, Seq. Id. No. 30, Seq. Id. No. 31, Seq. Id. No. 32, Seq. Id. No. 33, Seq. Id. No. 34, Seq. Id. No. 35, Seq. Id. No. 36, Seq. Id. No. 37, Seq. Id. No. 38, Seq. Id. No. 39, Seq. Id. No. 40, Seq. Id. No. 41, Seq. Id. No. 42, Seq. Id. No. 43, Seq. Id. No. 44, Seq. Id. No. 45, Seq. Id. No. 46, Seq. Id. No. 47, Seq. Id. No. 48, Seq. Id. No. 49, Seq. Id. No. 50, Seq. Id. No. 51, Seq. Id. No. 52, Seq. Id. No. 53, Seq. Id. No. 54, Seq. Id. No. 55, Seq. Id. No. 56, Seq. Id. No. 57, Seq. Id. No. 58, Seq. Id. No. 59, Seq. Id. No. 60, Seq. Id. No. 61, Seq. Id. No. 62, Seq. Id. No. 63, Seq. Id. No. 65, Seq. Id. 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No. 457, Seq. Id. No. 458, Seq. Id. No. 459, Seq. Id. No. 460, Seq. Id. No. 461, Seq. Id. No. 462, Seq. Id. No. 463, Seq. Id. No. 464, Seq. Id. No. 465, Seq. Id. No. 466, Seq. Id. No. 467, Seq. Id. No. 468, Seq. Id. No. 469, Seq. Id. No. 470, Seq. Id. No. 471, Seq. Id. No. 472, Seq. Id. No. 473, Seq. Id. No. 474, Seq. Id. No. 475, Seq. Id. No. 476, Seq. Id. No. 477, Seq. Id. No. 478, Seq. Id. No. 479, Seq. Id. No. 480, Seq. Id. No. 481, Seq. Id. No. 482, Seq. Id. No. 483, Seq. Id. No. 484, Seq. Id. No. 485, Seq. Id. No. 486, Seq. Id. No. 487, Seq. Id. No. 488, Seq. Id. No. 489, Seq. Id. No. 490, Seq. Id. No. 491, Seq. Id. No. 492, Seq. Id. No. 493, Seq. Id. No. 494, Seq. Id. No. 495, Seq. Id. No. 496, Seq. Id. No. 497, Seq. Id. No. 498, Seq. Id. No. 499, Seq. Id. No. 500, Seq. Id. No. 501, Seq. Id. No. 502, Seq. Id. No. 503, Seq. Id. No. 504, Seq. Id. No. 505, Seq. Id. No. 506, Seq. Id. No. 507, Seq. Id. No. 508, Seq. Id. No. 509, Seq. Id. No. 510, Seq. Id. No. 511, Seq. Id. No. 512, Seq. Id. No. 513, Seq. Id. No. 514, Seq. Id. No. 515, Seq. Id. No. 516 and Seq. Id. No. 517.
33. The method according to any of claims 27-30, wherein the autoantibody recognizes a mutated EGFR peptide that is selected from the group consisting of Seq. Id. No. 518, Seq. Id. No. 522, Seq. Id. No. 523, Seq. Id. No. 524, Seq. Id. No. 526, Seq. Id. No. 527, Seq. Id. No. 528, Seq. Id. No. 529, Seq. Id. No. 530, Seq. Id. No. 531, Seq. Id. No. 532, Seq. Id. No. 533, Seq. Id. No. 534, Seq. Id. No. 535, Seq. Id. No. 536, Seq. Id. No. 537, Seq. Id. No. 538, Seq. Id. No. 539, Seq. Id. No. 540, Seq. Id. No. 541, Seq. Id. No. 542, Seq. Id. No. 543, Seq. Id. No. 544, Seq. Id. No. 545, Seq. Id. No. 546, Seq. Id. No. 547, Seq. Id. No. 548, Seq. Id. No. 549, Seq. Id. No. 550, Seq. Id. No. 551, Seq. Id. No. 552, Seq. Id. No. 553, Seq. Id. No. 554, Seq. Id. No. 555, Seq. Id. No. 557, Seq. Id. No. 559, Seq. Id. No. 560, Seq. Id. No. 562, Seq. Id. No. 563, Seq. Id. No. 564, Seq. Id. No. 565, Seq. Id. No. 567, Seq. Id. No. 568, Seq. Id. No. 569, Seq. Id. No. 570, Seq. Id. No. 571, Seq. Id. No. 572, Seq. Id. No. 573, Seq. Id. No. 574, Seq. Id. No. 575, Seq. Id. No. 576, Seq. Id. No. 577, Seq. Id. No. 578, Seq. Id. No. 579, Seq. Id. No. 580, Seq. Id. No. 581, Seq. Id. No. 582, Seq. Id. No. 583, Seq. Id. No. 584, Seq. Id. No. 585, Seq. Id. No. 586, Seq. Id. No. 587, Seq. Id. No. 588, Seq. Id. No. 589, Seq. Id. No. 590, Seq. Id. No. 591, Seq. Id. No. 592, Seq. Id. No. 593, Seq. Id. No. 594, Seq. Id. No. 595, Seq. Id. No. 596, Seq. Id. No. 597, Seq. Id. No. 598, Seq. Id. No. 599 and Seq. Id. No. 601.
34. The method according to any of claims 27-30, wherein the autoantibody recognizes a mutated EGFR peptide that is selected from the group consisting of Seq. Id. No. 604, Seq. Id. No. 605, Seq. Id. No. 606, Seq. Id. No. 607, Seq. Id. No. 608, Seq. Id. No. 609, Seq. Id. No. 610, Seq. Id. No. 611, Seq. Id. No. 612, Seq. Id. No. 613, Seq. Id. No. 614, Seq. Id. No. 615, Seq. Id. No. 616, Seq. Id. No. 617, Seq. Id. No. 618 and Seq. Id. No. 619.
35. The method according to any of claims 27-34, wherein the level of an autoantibody in the blood sample of the human subject is 5 times higher than the level of said autoantibody representative for a human subject of a healthy population.
36. A method of diagnosis of non-small cell lung cancer in a human subject comprising:
a) measuring in a blood sample of the human subject a level of an autoantibody selected from the group of autoantibodies recognizing human EGFR,
b) comparing the level of said autoantibody to a reference level, and
c) providing a diagnosis of non-small cell lung cancer when the level of said autoantibody is above the reference level.
37. A method of diagnosis of non-small cell lung cancer in a human subject comprising:
a) measuring in a blood sample of the human subject a level of an autoantibody selected from the group of autoantibodies recognizing human EGFR,
b) comparing the level of said autoantibody to a reference level, and
c) recommending a treatment when the level of said autoantibody is above the reference level.
38. The method according to claim 36 or 37, wherein the autoantibody recognizes an EGFR peptide that is selected from the group consisting of Seq. Id. No. 3, Seq. Id. No. 8, Seq. Id. No. 9, Seq. Id. No. 10, Seq. Id. No. 11, Seq. Id. No. 12, Seq. Id. No. 13, Seq. Id. No. 14, Seq. Id. No. 64, Seq. Id. No. 102, Seq. Id. No. 309, Seq. Id. No. 370, Seq. Id. No. 373, Seq. Id. No. 519, Seq. Id. No. 520, Seq. Id. No. 521, Seq. Id. No. 525, Seq. Id. No. 556, Seq. Id. No. 558, Seq. Id. No. 561, Seq. Id. No. 566, Seq. Id. No. 600, Seq. Id. No. 602 and Seq. Id. No. 603.
39. The method according to any of claims 37-49, wherein the level of an autoantibody in the blood sample of the human subject is 5 times higher than the level of said autoantibody representative for a human subject of a healthy population.
40. The method according to any of claims 28-35, 37-39, wherein the treatment is erlotinib.
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